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Recent research has shown that mtDNA-deficient cancer cells (ρ 0 cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1 KO ) mice markedly delayed tumor formation after grafting ρ 0 cancer cells. Miro1 KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ 0 cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1 KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Direct-to-patient interventions enabling transitions from long-term benzodiazepine receptor agonist (BZRA) use to cognitive behavioral therapy for insomnia (CBTI) by older adults has the potential to reduce BZRA use and related harms while improving sleep outcomes without requiring prearranged clinician involvement., Objective: To compare 2 direct-to-patient behavior change interventions with treatment as usual (TAU) on BZRA use, sleep, and other health outcomes, and uptake of CBTI techniques., Design, Setting, and Participants: The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study was a 3-arm, pragmatic, open-label, minimum-contact, randomized clinical trial. The study began November 2020 and ended June 2022. Participants were randomly allocated to 1 of 3 groups, including 2 different mailed behavior change interventions or no intervention (TAU). Participants were from communities across the province of New Brunswick, Canada, and included adults 65 years and older living independently with long-term use of BZRAs and current or past insomnia., Interventions: The Sleepwell package (YAWNS-1) consisted of a cover letter and 2 booklets ("How to Stop Sleeping Pills" and "How to Get Your Sleep Back"). The other package (YAWNS-2) included updated versions of the 2 booklets ("You May Be at Risk" and "How to Get a Good Night's Sleep Without Medication") used in the Eliminating Medications Through Patient Ownership of End Results (EMPOWER) study., Main Outcomes and Measures: BZRA use at 6 months was the primary measure. Secondary measures included CBTI use, sleep, insomnia, daytime sleepiness, safety, anxiety, frailty, and quality of life., Results: A total of 1295 individuals expressed interest in the study, and 565 (43.6%) completed a baseline assessment. Participants had a mean (SD) age of 72.1 (5.7) years, a mean (SD) BZRA use duration of 11.4 (9.1) years, and 362 (64.1%) were female. Discontinuations and dose reductions of 25% or greater were highest with YAWNS-1 (50 of 191 [26.2%]; 39 of 191 [20.4%]; total, 46.6%) compared with YAWNS-2 (38 of 187 [20.3%]; 27 of 187 [14.4%]; total, 34.8%, P = .02) and TAU (14 of 187 [7.5%]; 24 of 187 [12.8%]; total, 20.3%, P < .001). YAWNS-1 also demonstrated better uptake of CBTI techniques and sleep outcomes compared with YAWNS-2 (new CBTI techniques: 3.1 vs 2.4; P =.03; sleep efficiency change: 4.1% vs -1.7%; P =.001) and reduced insomnia severity and daytime sleepiness compared with TAU (insomnia severity index change: -2.0 vs 0.3; P <.001; Epworth Sleepiness Scale change: -0.8 vs 0.3; P =.001)., Conclusions and Relevance: Results of the YAWNS NB randomized clinical trial show that, as a simple, scalable, direct-to-patient intervention, YAWNS-1 substantially reduced BZRA use and improved sleep outcomes. It could be implemented to transform insomnia care for older adults at the population level., Trial Registration: ClinicalTrials.gov Identifier: NCT04406103.

Background: Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown., Methods: We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs., Results: We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect., Conclusions: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Introduction: Research on the health of older Veterans in Canada is an emerging area. Few population-based studies in Canada have included older Veterans as a specific group of interest. This paper describes a cohort of self-identified Veterans within the Canadian Longitudinal Study on Aging (CLSA)., Materials and Methods: Using data from the CLSA baseline assessment (2011-2015), we describe sociodemographic and health characteristics along with military-related variables in a cohort of Veterans in Canada. We also estimate the number of Canadian and non-Canadian Veterans living in Canada at the time of the CLSA baseline data collection., Results: We estimate that at the CLSA baseline, there were 718,893 (95% confidence interval [CI], 680,033-757,110) Canadian Veterans and 185,548 (95% CI, 165,713-205,100) non-Canadian Veterans aged 45-85 years living in Canada. Veterans were older and predominantly male compared to non-Veterans in the CLSA. Following age and sex adjustment, the distribution of sociodemographic and health characteristics was similar across all groups. The majority (> 85%) of participants in each comparison group reported self-rated general and mental health as excellent, very good, or good. Following age and sex adjustment, most characteristics across groups remained similar. One exception was mental health, where a greater proportion of Veterans screened positive for depression and anxiety relative to non-Veterans., Conclusions: Using CLSA baseline data, we estimate the number of older Veterans in Canada and present descriptive data that highlight interesting differences and similarities between Veterans and non-Veterans living in Canada. Canadian and non-Canadian Veterans in the CLSA are presented separately, with the latter group having not been previously studied in Canada. This paper presents a snapshot of a cohort of self-identified Veterans within the CLSA at study baseline and highlights the potential of the CLSA as a vehicle for studying the aging Veteran population in Canada for years to come., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Little is known about demographic and environmental factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Objective: To investigate factors associated with MOGAD using a case-control design and validated questionnaire from the Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS)., Methods: We enrolled patients with positive MOG antibody serology and diagnosis of MOGAD at six Canadian centres. MOGAD participants completed the EnvIMS questionnaire, and were compared to unaffected controls from the Canadian arm of EnvIMS. We calculated crude and adjusted odds ratios (OR) using logistic regression models and Firth's procedure for rare events., Results: We enrolled 39 MOGAD participants with mean (SD) age 45.0 (14.4) years, 28 (71.8 %) women, 25 (64.1 %) White, 26 (66.7 %) residents of Ontario, and mean BMI 28.6 (7.1). They were compared to 956 controls. Using multivariable logistic regression, larger body size at age 10 years (OR: 3.57, 95 % CI:1.23 - 10.33) and non-White ethnicity (OR:3.81, 95 % CI:1.93-7.54) were associated with higher odds of MOGAD. Among Ontario residents, current BMI ≥30 was associated with higher odds of MOGAD (OR:2.79, 95 % CI:1.03-7.53)., Conclusion: Our findings are hypothesis-generating due to the sample size, but suggest that obesity and ethnicity should be explored as potential risk factors for MOGAD in other settings., Competing Interests: Declaration of Competing Interest Sam Hosseini-Moghaddam has nothing to disclose. Ruth Ann Marrie receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, US Department of Defense and the Arthritis Society. She is supported by the Waugh Family Chair in Multiple Sclerosis. She is a co-investigator on a study funded in part by Biogen Idec and Roche (no funds to her/her institution). Christina Wolfson receives research funding from CIHR, Multiple Sclerosis Society of Canada, and the Canada Foundation for Innovation. Robert Carruthers is Site Investigator for studies funded by Roche, Novartis, VieloBio, Serono and receives research support from Teva Innovation Canada, Roche Canada and Vancouver Coastal Health Research Institute. RC has received honoraria from Roche, EMD Serono, Sanofi, Biogen, Novartis, and Alexion. Mark Freedman has received research or educational grants from Sanofi-Genzyme Canada. He has received honoraria or consultation fees from Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD Inc., Hoffman La-Roche, Janssen (J&J), Merck Serono, Novartis, Sanofi-Genzyme, and Teva Canada Innovation. He has served as a member of an advisory board or board of directors for Alexion, Atara Biotherapeutics, BayerHealthcare, Beigene, BMS (Celgene), Celestra, Hoffman La-Roche, Janssen (J&J), McKesson, Merck Serono, Novartis, Sanofi-Genzyme. He has participated in a speaker's bureau for Sanofi-Genzyme and EMD Serono. Sarah Morrow has served as an advisory board member or received consulting fees from Biogen Idec; Bristol Myers Squibb/Celgene; EMD Serono; Novartis; Roche; Sanofi Genzyme; Teva Neurosciences. She has participated in a speaker's bureau for Biogen Idec; Bristol Myers Squibb/Celgene; EMD Serono; Novartis; Roche; Sanofi Genzyme. She has received research support from Biogen Idec; Novartis; Roche; Sanofi Genzyme. She has participated as a site investigator in clinical trials sponsored by AbbVie; Bristol Myers Squibb/Celgene; EMDSerono; Novartis; Genzyme; Roche; Sanofi Genzyme. Liesly Lee is a site investigator for studies funded by Roche, Novartis and Sanofi Aventis. He has received consultation fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Roche and Sanofi Aventis. Rosane Nisenbaum has nothing to disclose. Andrea Konig has nothing to disclose. Sandra Magalhaes has nothing to disclose. Dalia L. Rotstein has received research support from the MS Society of Canada, Consortium of Multiple Sclerosis Centers (CMSC), National MS Society, University of Toronto Division of Neurology and Roche Canada. She has received speaker or consultant fees from Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis., (Copyright © 2023. Published by Elsevier B.V.)

Background: Although legislation permits New Brunswick pharmacy professionals to administer a wide range of immunizations, public funding for these services is currently limited to immunizations against influenza and COVID-19 and was recently extended to include pneumococcal immunization (Pneu23) in individuals aged 65 years or older. We used administrative data to project health and economic outcomes associated with the current Pneu23 program and with extension of public funding to include: 1) younger adults aged 19 years or older in the Pneu23 program, and 2) tetanus boosters (Td/Tdap)., Methods: Two model scenarios were compared: a Physician-Only model in which physicians remain the only practitioners to administer publicly funded Pneu23 and Td/Tdap, and a Blended model in which this service is also provided by pharmacy professionals. Immunization rates by practitioner type were projected based on physician billing data accessed via the New Brunswick Institute for Research, Data and Training in conjunction with trends observed with influenza immunization by pharmacists. These projections were used along with published data to estimate health and economic outcomes under each model., Results: Public funding of Pneu23 (65+), Pneu23 (19+) and Td/Tdap (19+) administration by pharmacy professionals is projected to yield increased immunization rates and physician time savings compared with the Physician-Only model. Public funding of Pneu23 and Td/Tdap administration by pharmacy professionals in those aged ≥19 years would result in cost savings, owing primarily to productivity losses avoided in the working age population., Discussion: Increased immunization rates, physician time savings and cost savings may be realized if public funding were extended to include administration of Pneu23 in younger adults and Td/Tdap, by pharmacy practitioners., Competing Interests: The authors have no conflicts of interest., (© The Author(s) 2023.)

Background: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established., Objective: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design., Methods: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events., Results: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche., Conclusion: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

Background: Characterizing the prevalence and distribution of frailty within a population can help guide decision-making and policy development by identifying health service resource needs. Here we describe the prevalence of frailty among hospitalized older adults in New Brunswick (NB), Canada., Methods: NB administrative hospital claims data were used to identify hospitalized older adults aged 65 or older between April 1, 2017 and March 31, 2019. Frailty was quantified using the Hospital Frailty Risk Score (HFRS), a validated frailty tool derived from claims data. Individuals with a HFRS ranked as intermediate or high were categorized as frail. The distribution of frailty across sex and age are described. Crude prevalence estimates and corresponding 95% confidence intervals are presented., Results: A total of 55,675 older adults (52% females) were hospitalized. The overall prevalence of frailty was 21.2% (95%CI: 20.9-21.6). Prevalence increased with age: 12.7% (95%CI: 12.3-13.1) in the 65-74 age group, 24.7% (95%CI: 24.1-25.3) in the 75-84 age group and 41.6% (95%CI: 40.6-42.7) for those aged 85 and over ( p <.001)., Discussion/conclusion: The distribution of frailty is in line with that reported in other jurisdictions. We demonstrate the feasibility of the HFRS to identify and characterize frailty in a large sample of older adults who were hospitalized, using administrative data., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood the Canadian Geriatrics Journal’s policy on conflicts of interest disclosure and declare no conflicts of interest., (© 2022 Author(s). Published by the Canadian Geriatrics Society.)

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence. Abbreviations : AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A 1 ; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.

Background: Chronic benzodiazepine receptor agonist (BZRA) use among older adults is a public health concern given cognitive and physical risks. One in four older adults in New Brunswick, Canada, is a long-term user of BZRAs. Previous studies using a direct-to-patient approach as the primary intervention target have shown promise in reducing BZRA use. The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study aims to reduce the long-term use of BZRAs in older adults and increase the use of cognitive behavioural therapy for insomnia (CBTi), which is the recommended first line treatment., Methods: The trial (ClinicalTrials.gov registration NCT04406103) is a three arm, open-label, parallel randomized controlled trial in NB, Canada. Eligible participants 65 years and older using BZRAs long-term will be randomly allocated to: the Eliminating Medications through Patient Ownership of End Results (EMPOWER) information package group; the Sleepwell information package group; or treatment-as-usual (TAU). Information packages will be mailed via Canada Post. The primary outcome of BZRA discontinuation at 6 months will be compared across groups. Secondary outcomes include participants with ≥25% BZRA dose reduction, and switching to newly prescribed alternate sedative-hypnotics. Several exploratory outcomes will also be examined., Discussion: Targeting participants with information packages informing them of appropriate use, dangers, and approaches to reducing BZRA use and increasing CBTi use may be beneficial in a region of Canada with the highest rate of chronic BZRA use in older adults. Comparing information packages and TAU will provide insights into the effectiveness of direct-to-patient interventions for BZRA reduction., Competing Interests: None., (© 2022 The Authors.)

Introduction: Children with medical complexity and their families are an important population of interest within the Canadian healthcare system. Despite representing less than 1% of the paediatric population, children with medical complexity require extensive care and account for one third of paediatric healthcare expenditures. Opportunities to conduct research to assess disparities in care and appropriate allocation of health resources relies on the ability to accurately identify this heterogeneous group of children. This study aims to better understand the population of children with medical complexity in the Canadian Maritimes, including Nova Scotia (NS), New Brunswick (NB) and Prince Edward Island (PEI). This will be achieved through three objectives: (1) Evaluate the performance of three algorithms to identify children with medical complexity in the Canadian Maritimes in administrative data; then using the 'best fit' algorithm (2) Estimate the prevalence of children with medical complexity in the Canadian Maritimes from 2003 to 2017 and (3) Describe patterns of healthcare utilisation for this cohort of children across the Canadian Maritimes., Methods and Analysis: The research will be conducted in three phases. In Phase 1, an expert panel will codevelop a gold-standard definition of paediatric medical complexity relevant to the Canadian Maritime population. A two-gate validation process will then be conducted using NS data and the gold-standard definition to determine the 'best fit' algorithm. During phase 2 the 'best fit' algorithm will be applied to estimate the prevalence of children with medical complexity in NS, NB and PEI. Finally, in phase 3 will describe patterns of healthcare utilisation across the Canadian Maritimes., Ethics and Dissemination: Ethics approval for this protocol was granted by the institutional research ethics board at the IWK Health Centre (REB # 1026245). A waiver of consent was approved. This study will use an integrated knowledge translation approach, where end users are involved in each stage of the project, which could increase uptake of the research into policy and practice. The findings of this research study will be submitted for publication and dissemination through conference presentations and with our end users., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lower levels of sun exposure in childhood have been suggested to be associated with increased risk of multiple sclerosis (MS). In this paper we extend previous work, using two novel analytical strategies., Methods: Data collected in the Environmental risk factors In MS (EnvIMS) study, a case-control study with MS cases and population-based controls from Canada, Italy and Norway, were used. Participants reported on sun exposure behaviours for 5-year age intervals from birth; we focused on the first three age intervals (≤15 years). We compared two life course epidemiology conceptual models, the critical period and the accumulation model. We also used latent class analysis to estimate MS risk for different latent sun exposure behaviour groups., Results: The analyses included 2251 cases and 4028 controls. The accumulation model was found to be the best model, which demonstrated a nearly 50% increased risk of MS comparing lowest reported summer sun exposure with highest [risk ratio (RR) = 1.47 (1.24, 1.74)]. The latent sun exposure behaviour group, characterized by low sun exposure during summer and winter and high sun protection use, had the highest risk of MS; a 76% increased risk as compared with the group with high sun exposure and low sun protection use [RR = 1.76 (1.27, 2.46)]., Conclusions: Our analyses provide novel insights into the link between sun exposure and MS. We demonstrate that more time indoors during childhood and early adolescence is linked with MS risk, and that sun protection behaviours in those who spend most time indoors may play a key role in increasing risk., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: While studying the etiology of multiple sclerosis (MS) in children has several methodological advantages over studying etiology in adults, studies are limited by small sample sizes., Objective: Using a rigorous methodological process, we developed the Pediatric MS Tool-Kit, a measurement framework that includes a minimal set of core variables to assess etiological risk factors., Methods: We solicited input from the International Pediatric MS Study Group to select three risk factors: environmental tobacco smoke (ETS) exposure, sun exposure, and vitamin D intake. To develop the Tool-Kit, we used a Delphi study involving a working group of epidemiologists, neurologists, and content experts from North America and Europe., Results: The Tool-Kit includes six core variables to measure ETS, six to measure sun exposure, and six to measure vitamin D intake. The Tool-Kit can be accessed online ( www.maelstrom-research.org/mica/network/tool-kit )., Conclusion: The goals of the Tool-Kit are to enhance exposure measurement in newly designed pediatric MS studies and comparability of results across studies, and in the longer term to facilitate harmonization of studies, a methodological approach that can be used to circumvent issues of small sample sizes. We believe the Tool-Kit will prove to be a valuable resource to guide pediatric MS researchers in developing study-specific questionnaire.

Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mitochondria and oxidative phosphorylation (OXPHOS) are emerging as intriguing targets for the efficient elimination of cancer cells. The specificity of this approach is aided by the capacity of non-proliferating non-cancerous cells to withstand oxidative insult induced by OXPHOS inhibition. Recently we discovered that mitochondrial targeting can also be employed to eliminate senescent cells, where it breaks the interplay between OXPHOS and ATP transporters that appear important for the maintenance of mitochondrial morphology and viability in the senescent setting. Hence, mitochondria/OXPHOS directed pharmacological interventions show promise in several clinically-relevant scenarios that call for selective removal of cancer and senescent cells.

Introduction: Ambient particulate air pollution is known to have detrimental effects on cardiovascular health but less is known about the specific effects of black carbon or elemental carbon (BC/EC) and ultrafine particles (UFP)., Methods: We present a narrative review of the epidemiological evidence related to the impact of exposure to BC/EC and UFP on blood pressure in adults. We searched PubMed and EMBASE in September 2017, using a predefined search strategy. Abstracts were screened using predefined inclusion criteria. Data collection was completed using a standard data extraction form. We focused on main effect estimates for associations between short (≤7 days) and long-term exposures to BC/EC and UFP and systolic (SBP) and diastolic blood pressure (DBP). Effect estimates were rescaled to enable direct comparisons between studies., Results: Thirty publications were included in the review: 19 studies examined outdoor exposure to BC/EC, 11 examined outdoor UFP, three studies examined indoor BC and one study examined indoor UFP. In general, existing evidence supports a positive association between BC/EC and blood pressure. Evidence for outdoor UFP exposures were less clear as effect estimates were small in magnitude and confidence intervals often included the null., Conclusions: Existing evidence supports a positive association between BC/EC and blood pressure in adults, whereas UFPs do not appear to have a meaningful impact on blood pressure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The world is aging and we must face the challenges that this brings. One of the reasons for the increasing aging of the world's population is the increase in life expectancy and, since we live longer, it is of paramount importance to live well and to prevent age-associated diseases. In this way, it is crucial to improve knowledge of the aging process and of the mechanisms that contribute to it. Ideally it would be of great interest to have a panel of biomarkers of healthy aging that would allow an estimate of the biological age of an individual. One of the changes that greatly contribute to aging is the loss of protein homeostasis, also called proteostasis. To ensure the proper function of cells and to maintain cellular proteostasis, organisms have developed systems to control protein synthesis, folding and degradation. Loss or dysfunction of proteostasis is at the root of many well-studied human neurological diseases, such as Alzheimer's disease and, more recently, it has been implicated in the aging process with some reports showing long-lived animals to have improved proteostasis. Growing evidence suggests a strong link between modifications in the quantity and/or activity of several players involved in proteostasis and longevity. In this review, we give an overview of the main characteristics of aging with focus on proteostasis. We present how changes in components of proteostasis, during aging, impact the lifespan of model organisms. We also briefly review the current state of aging biomarkers and discuss the potential of proteostasis network components as markers of healthy aging., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting., Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS., Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale., Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09)., Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education., Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size., Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors., Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded., Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk., (© The Author(s), 2015.)

Background: Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age., Objective: The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk., Methods: In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood., Results: Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70)., Conclusions: These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS., (© The Author(s), 2015.)

Query of sun-related habits or ancestry could help screen for risk of vitamin D insufficiency (serum 25-hydroxyvitamin D<75nmol/L). We evaluated the association between Sun Exposure Score (calculated from recall of Time Exposed to Sun and Skin Exposed to Sun in the previous week), demographics and anthropometrics (including self-reported ancestry and skin melanin reflectometry), and serum 25(OH)D levels in healthy young Canadian adults in the Greater Toronto Area (GTA; 43°N) during fall. 310 adults (67% female) of European, East Asian, and South Asian ancestries were evaluated. The median (interquartile range) 25(OH)D level was 49.7nmol/L (36.7-70.3) and 80% of participants were vitamin D insufficient. The vast majority of those of East and South Asian ancestry were vitamin D insufficient (91% and 97%, respectively), as were 55% of those of European ancestry. Sun Exposure Score and 25(OH)D concentrations were not associated after accounting for confounders. A multivariable model showed ancestry, recent summer sun exposure, sex, melanin, vitamin D intake, age and year of study significantly predicted 25(OH)D concentration; ancestry was the strongest independent predictor (adjusted R(2)=43%). Although Sun Exposure Score was not a significant predictor of serum 25(OH)D levels, inquiry of ancestry has potential use in screening for vitamin D insufficiency., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Obesity may be a risk factor for developing multiple sclerosis (MS)., Objective: We examined if body size influences the risk of MS in a population-based, case control study., Methods: A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity., Results: In Norway a large body size (silhouettes 6-9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09-4.46 for men and OR 1.43; 95% CI 0.90-2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68-4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy., Conclusions: Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy., (© The Author(s), 2014.)

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system, often resulting in significant neurological disability. The causes of MS are not known; however, the incidence of MS is increasing, thereby suggesting that changes in lifestyle and/or environmental factors may be responsible. On this background, the Environmental Risk Factors in MS Study or EnvIMS study was designed to further explore the etiology of MS. The design and methodology are described, providing details to enable investigators to (i) use our experiences to design their own studies; (ii) take advantage of, and build on the methodological work completed for, the EnvIMS study; (iii) become aware of this data source that is available for use by the research community., Methods: EnvIMS is a multinational case-control study, enrolling 2,800 cases with MS and 5,012 population-based controls in Canada, Italy, Norway, Serbia and Sweden. The study was designed to investigate the most commonly implicated risk factors for MS etiology using a self-report questionnaire., Results/conclusions: The use of a common methodology to study MS etiology across several countries enhances the comparability of results in different geographic regions and research settings, reduces the resources required for study design and enhances the opportunity for data harmonization., (© 2015 S. Karger AG, Basel.)

Objectives: For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Pediatric-onset MS provides an opportunity to study early disease processes., Methods: Using antigen microarrays, including CNS-related proteins, lipids, and other autoantigens, we studied early immunologic events involved in clinical onset of pediatric MS. Serum samples were collected at the time of incident acquired CNS demyelinating syndromes (ADS) in children who, in subsequent prospective follow-up, were ascertained to have either pediatric MS (ADS-MS) or a monophasic illness (ADS-mono). Samples were obtained both at the time of ADS presentation and 3 months into follow-up. We used an initial training set of samples to implicate antibody signatures associated with each group, and then a test set. An additional set of follow-up samples (stability set) was used as a form of internal validation., Results: Children with ADS-MS tended to have distinguishable serum antibody patterns both at the time of ADS presentation and 3 months into follow-up. At the time of ADS, serum samples from patients with ADS-MS or ADS-mono reacted against similar numbers of CNS antigens, although CNS antigens implicated in adult MS were more often targeted in children with ADS-MS. The follow-up ADS-MS samples reacted against a broader panel of CNS antigens, while corresponding ADS-mono samples exhibited a contraction of the initial antibody response., Conclusions: Our findings in this prospective cohort of pediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions., (© 2014 American Academy of Neurology.)

Depression--be it a formal diagnosis based on consensus clinical criteria, or a collection of symptoms revealed by a self-report rating scale--is common in patients with multiple sclerosis (MS) and adds substantially to the morbidity and mortality associated with this disease. This Review discusses the prevalence and epidemiology of depression in patients with MS, before covering aetiological factors, including genetics, brain pathology, immunological changes, dysregulation of the hypothalamic-pituitary-adrenal axis, and psychosocial influences. Treatment options such as antidepressant drugs, cognitive-behavioural therapy, mindfulness-based therapy, exercise and electroconvulsive therapy are also reviewed in the context of MS-related depression. Frequent comorbid conditions, namely pain, fatigue, anxiety, cognitive dysfunction and alcohol use, are also summarized. The article then explores three key challenges facing researchers and clinicians: what is the optimal way to define depression in the context of diseases such as MS, in which the psychiatric and neurological symptoms overlap; how can current knowledge about the biological and psychological underpinnings of MS-related depression be used to boost the validity of this construct; and can intervention be made more effective through use of combination therapies with additive or synergistic effects, which might exceed the modest benefits derived from their individual components?

In 2012, about 16487 people received kidney transplants in the United States, whereas 95022 candidates were on the waiting list by the end of the year. Despite advances in renal transplant immunology, approximately 40% of recipients will die or lose graft within 10 years. The limitations of current therapies for renal failure have led researchers to explore the development of modalities that could improve, restore, or replace the renal function. The aim of this paper is to describe a reasonable approach for kidney regeneration and review the current literature regarding cell sources and mechanisms to develop a bioengineering kidney. Due to kidneys peculiar anatomy, extracellular matrix based scaffolds are rational starting point for their regeneration. The perfusion of detergents through the kidney vasculature is an efficient method for delivering decellularizing agents to cells and for removing of cellular material from the tissue. Many efforts have focused on the search of a reliable cell source to provide enrichment for achieving stable renal cell systems. For an efficient bioengineered kidney, these cells must be attached to the organ and then maturated into the bioractors, which simulates the human body environment. A functional bioengineered kidney is still a big challenge for scientists. In the last ten years we have got many improvements on the field of solid organ regeneration; however, we are still far away from the main target. Currently, regenerative centers worldwide have been striving to find feasible strategies to develop bioengineered kidneys. Cell-scaffold technology gives hope to end-stage renal disease patients who struggle with morbidity and mortality due to extended periods on dialysis or immunosupression. The potential of bioengineered organ is to provide a reliable source of organs, which can be refunctionalized and transplanted.

Objectives: The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy., Methods: A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence., Results: A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16-2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03-1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08-1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06-2.63) and blonde hair (OR 1.36, 95% CI 1.09-1.70) were associated with MS after adjusting for outdoor activity and sunscreen use., Conclusion: Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk., (© The Author(s) 2014.)

Background: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS)., Methods: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM)., Results: IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66)., Conclusions: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation.

The authors collected demographic, clinical, and neuroimaging data prospectively on 38 children with transverse myelitis. One child died during the illness. The female:male ratio was 1.2:1 for children under age 10 years and 2.6:1 over age 10 years. Twenty-eight (74%) reported a prodromal event. Twenty-two patients (58%) had longitudinally extensive transverse myelitis, 9 (24%) had focal lesions, and 5 (13%) had both. Twenty of 33 with brain imaging (61%) had brain lesions; 7 fulfilled McDonald criteria for dissemination in space. Seven of 22 (36%) tested had cerebrospinal fluid oligoclonal banding, 6 of whom had brain lesions. Serum neuromyelitis optica IgG antibodies were absent in all 20 of the children for whom this test was available. At follow-up (mean 3.2 ± 2.0 years), 16% are wheelchair-dependent, 22% have persisting bladder dysfunction, and 13% have been diagnosed with multiple sclerosis.

Decreasing research funding is in conflict with the increasing need to conduct large studies to examine rare risk factors and interactions between risk factors. As a result, investigators are searching for strategies to stretch research funds and to design studies that will maximize investments already made. Multiple sclerosis (MS) is generally accepted as a multifactorial disease, and the assessment of interactions between risk factors and the desire to assess risk factors within particular sub-groups requires a large number of participants. Harmonization is a methodology that may help address this problem. Harmonization is a methodological approach that aims to systematize the process of combining individual data that are collected in several observational studies. Combining data will increase sample size, but the quality of the harmonized result is only as high as the quality of the individual studies and the comparability of the constructs measured. In this short report, we introduce the concept of harmonization and provide examples where harmonization may be advantageous in MS research., (© 2012 John Wiley & Sons A/S.)

Objective: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases., Methods: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry., Results: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels., Conclusions: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Background: HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children., Methods: In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use., Findings: Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61-4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99-222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26-273·85) or CSF oligoclonal bands (6·33, 3·35-11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%., Interpretation: Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness., Funding: Canadian Multiple Sclerosis Scientific Research Foundation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Multiple sclerosis (MS) in the pediatric age group is being increasingly recognized. In adults, complex interactions between genetic and environmental factors contribute to risk and the major genetic component of MS susceptibility localizes to the major histocompatibility complex (human leukocyte antigen [HLA]). Whether HLA alleles predict MS in at-risk children presenting with acquired demyelinating syndromes (ADS) of the CNS is unknown., Methods: HLA-DRB1 alleles were typed using an allele-specific PCR amplification method on samples from 266 children presenting with ADS enrolled in the prospective Canadian Pediatric Demyelinating Disease Study and from 196 healthy controls., Results: Sixty-four of 266 children with ADS met established criteria for a diagnosis of MS during a mean follow-up of 3.2 ± 1.5 years. Children harboring DRB1*15 alleles were more likely to be diagnosed with MS (χ(2) = 12.2, p < 0.001; OR = 2.7), an observation strengthened by children of European ancestry (χ(2) = 10.5, p = 0.001; OR = 3.3). DRB1*15 allele frequencies in children with ADS of European ancestry subsequently diagnosed with MS were greater than in children with monophasic ADS (χ(2) = 10.7, p = 0.001) or healthy controls (χ(2) = 12.5, p < 0.001). The proportion of children with non-European ancestry diagnosed with MS was not influenced by DRB1*15 status., Conclusion: DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to MS risk in both pediatric- and adult-onset disease. The specificity of the DRB1*15 risk allele for children with subsequent MS diagnosis, but not for all children with ADS, indicates that the risk conveyed by DRB1*15 relates to chronic CNS disease (MS), rather than acquired demyelination in general.

Aim: To describe the neonatal symptoms, developmental problems and chronic multisystem medical morbidities of congenital myotonic dystrophy (CDM) patients registered in the United States National Registry of Myotonic Dystrophy - a disease-specific, self-report program maintained since 2002. Comparisons with the Canadian Paediatric Surveillance Program for CDM are highlighted., Methods: Genetically confirmed cases of CDM demonstrating symptoms in the first four weeks of life are described. Patients (or their caregivers) and physicians completed survey information at baseline and annually thereafter., Results: Twenty-one patients were included (13 male and eight female), ranging from three to 24 years of age. The CTG trinucleotide repeat number ranged from 940 to 2100. Gastrointestinal, pneumonia and cardiac morbidities were most common. No deaths were noted., Conclusions: The United States Registry is a valuable resource for clinical research on patients with CDM; however, in contrast with the Canadian Paediatric Surveillance Program, some limitations are identified.

Background: Multiple factors, in addition to left ventricular ejection fraction (LVEF) influence the risk of mortality in coronary artery disease. The purpose of this study was to evaluate the main causes of syncope after myocardial infarction (MI) and to propose an algorithm of management., Methods: 356 patients consecutively admitted for syncope and history of MI (>1 month), without ventricular tachycardia (VT), underwent echocardiography, Holter monitoring, head-up tilt test, exercise testing, signal-averaged ECG, electrophysiological study (EPS) and evaluation of coronary status. The mean follow-up was 4±2 years., Results: Monomorphic VT, ventricular flutter or fibrillation (VF) and supraventricular tachyarrhythmia were respectively induced at EPS in 87, 63 and 39 patients; conduction disturbances were noted in 23 patients, and 57 patients had several abnormalities. Among the 144 patients with negative EPS, coronary ischaemia was identified in 37 patients, and hypervagotonia in 27 patients. All studies remain negative in 84 patients (23.6%), more frequently women (p<0.001). Four patients died suddenly during follow-up. A longer QRS duration, a lower LVEF and grade IVa,b of Lown on Holter ECG were associated with the induction of VT. LVEF<40% and VT/VF induction were predictors of cardiac mortality, VT was a predictor of sudden death, and low LVEF and advanced age were predictors of death by heart failure., Conclusion: Myocardial ischaemia, hypervagotonia, conduction abnormalities, ventricular or supraventricular tachyarrhythmias were identified in 76% of patients with syncope after MI. Several factors of syncope were found in 57 patients (16%). Non-invasive rhythmological and systematic coronary status assessment should be recommended in patients with syncope following MI.

Background: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS)., Objective: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS., Methods: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children., Results: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66-18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3., Conclusion: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Fascicular ventricular tachycardia (VT), the commonest form of idiopathic left VT, occurs more frequently in young males without structural heart disease and usually presents as paroxysmal palpitations. It is subdivided into two more common subtypes, posterior and anterior. A macro-reentrant circuit involving a considerable and variable extent of the left interventricular septum is presumed to be the underlying arrhythmogenic mechanism. A slow conduction zone with particular sensitivity to verapamil participates in the circuit and it seems that diastolic potentials (DP) represent the electrical activity in or near this zone. The fascicles of the left bundle appear to constitute part of the retrograde pathway and Purkinje potentials (PP) are assumed to represent their activation. In the present retrospective study, the authors review twelve cases of fascicular VT (ten posterior and two anterior) evaluated in the electrophysiology laboratory. Although initial induction was obtained in all patients, reproducibility was poor as a consequence of frequent contact inhibition during endocardial mapping of the left ventricle and this meant that ablation was not possible in two cases. Two cases of associated atrioventricular nodal reentrant tachycardia (AVNRT) and a case of associated atrioventricular reentrant tachycardia by a right posterior accessory pathway were documented, which suggest a correlated anatomic substrate. After ablation of the slow nodal pathway in one of the AVNRTs, fascicular VT was no longer inducible. Ablation of the fascicular VT was attempted in nine patients, at the tachycardia exit site (characterized by an early ventricular electrogram fused with a Purkinje potential) in two patients with anterior fascicular VT and in five patients with the posterior subtype, and near the slow conduction pathway (site with simultaneous recording of DP and PP) in the other two patients. The initial success rate with a single procedure was 78%, two of the ablations at the tachycardia exit site failing, with no complications. If we include the success of a repeated case with three-dimensional mapping, the overall success rate was 80%. Ablation of fascicular tachycardia appears to be a good therapeutic option with a good success rate and without significant adverse events. The poor reproducibility as a consequence of contact inhibition during endocardial left ventricular mapping is the principal limiting factor. With the help of currently available mapping systems, we hope that this limitation will disappear, as it is now possible with some devices to acquire accurate information on suitable sites for subsequent radiofrequency application with little or no contact, facilitating the ablation procedure. Ablation at a site with simultaneous recording of DP and PP is considered by most authors to be more effective than that performed at the tachycardia exit site.

Objectives: The rate of pressure rise (dP/dtmax) has mainly been studied in the left ventricle (LV), where it was demonstrated to be highly dependent of preload, but independent of afterload. Load dependence of right ventricular (RV) dP/dtmax is assumed to be similar to (LV)dP/dtmax, although this issue has not yet been investigated in detail. In the current study, we evaluated acute afterload dependence of dP/dtmax in both ventricles in rats., Methods and Results: Adult Wistar rats (n = 8) were instrumented to record RV and LV pressures and septal-free wall diameters. RV and LV afterload elevations were performed by beat-to-beat graded constrictions of the pulmonary trunk or aortic root, respectively. Control cycles and low, moderate and high (isovolumetric) afterload levels were analysed. In both ventricles, afterload modulation of dP/dt was assessed by dP/dtmax normalized for end-diastolic dimensions (dP/dtmax/EDD) and by peak and mean accelerations of pressure rise. RV afterload elevation increased dP/dtmax, dP/dtmax/EDD, peak and mean acceleration of RV pressure rise, without changing the time from end-diastole to dP/dtmax. LV afterload elevations did not significantly change the corresponding left-sided parameters., Conclusions: In this study we demonstrated that, in contrast to the left ventricle, right ventricular dP/dtmax and dP/dtmax/EDD relation are significantly afterload sensitive. This should be taken into account for its application in the haemodynamic evaluation of cardiac function in experimental and clinical settings.