Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis.

BACKGROUND: Axonal degeneration and neuronal loss have been described as the major causes of irreversible clinical disability in multiple sclerosis (MS). The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) protein has been associated with neuroprotection in models of ischemia and neuronal responses to stressors. METHODS: To characterize its potential to influence inflammatory neurodegeneration, we examined ARNT2 expression in the experimental autoimmune encephalomyelitis (EAE) model of MS and characterized mediators that influence ARNT2 expression as well as plausible partners and targets. RESULTS: Arnt2 message and protein levels dropped significantly in EAE spinal cords as disease developed and were lowest at peak disability. ARNT2 expression is prominent in neuronal cell bodies within the gray matter with some staining in glial fibrillary acidic protein (GFAP)+ astrocytes in healthy animals. At peak disease, ARNT2 expression is reduced by 20-50% in gray matter neurons compared to healthy controls. ARNT2 intensity in neurons throughout the EAE spinal cord correlated inversely with the degree of immune cell infiltration (r = - 0.5085, p < 0.01) and axonal damage identified with SMI32 staining (r = - 0.376, p = 0.032). To understand the relationship between ARNT2 expression and neuronal health, we exposed enriched cortical cultures of neurons to hydrogen peroxide (H2O2) to mimic oxidative stress. H2O2 at lower doses rapidly increased ARNT2 protein levels which returned to baseline within 3-4 h. Exposure to higher doses of H2O2) dropped ARNT2 levels below baseline, preceding cytotoxicity measured by morphological changes and lactate dehydrogenase release from cells. Decreases in ARNT2 secondary to staurosporine and H2O2 preceded increases in cleaved caspase 3 and associated apoptosis. We also examined expression of neuronal pas 4 (Npas4), whose heterodimerization with ARNT2 drives expression of the neurotrophic factor brain-derived neurotrophic factor (Bdnf). Like ARNT2, Npas4 levels also decline at the onset of EAE and are linked to decreases in Bdnf. In vitro, H2O2 exposure drives Npas4 expression that is tied to increases in Bdnf. CONCLUSION: Our data support ARNT2 as a neuronal transcription factor whose sustained expression is linked to neuronal and axonal health, protection that may primarily be driven through its partnering with Npas4 to influence BDNF expression.

Public Health Considerations Associated with the Location and Operation of Off-Leash Dog Parks.

Off-leash dog parks may enhance human health, but may also lead to health risk through infection or canine aggression. Published evidence was reviewed to examine positive and negative public health impacts of off-leash dog parks, as well as strategies for enhancing benefits and mitigating risks. Evidence suggests that off-leash dog parks can benefit physical and social health, as well as community connectedness. While studies have documented shedding of zoonotic agents in dog parks, the risk of transmission to humans is relatively unknown. Evidence on the risk of dog bites in off-leash dog parks is also limited. Case-examples from North American off-leash dog parks highlight the importance of park location/design, public adherence to safe and hygienic practices, and effective regulatory strategies for mitigating potential risks and maximizing the benefits of off-leash dog parks.

The Importance of Disease-Free Survival as a Clinical Trial Endpoint: A Qualitative Study Among Canadian Survivors of Lung Cancer.

BACKGROUND: In lung cancer trials, overall survival is a well-validated and widely used endpoint; yet, in the context of adjuvant or curative intent treatments, disease-free survival (DFS) may be a better indicator of transformative patient outcomes. Although use of DFS is growing, patient perceptions of its relevance have not been established. OBJECTIVE: We aimed to understand the importance of DFS as a trial endpoint, from the perspective of survivors of lung cancer. METHODS: Web-based qualitative interviews were conducted with Canadian survivors of stage Ib-IIIa lung cancer. Participants described their experiences of cancer diagnosis and treatment, including their treatment goals and priorities. Participants then provided their perspectives on DFS and overall survival, and how well each aligned with their treatment priorities. Thematic analysis was used to explore patterns in responses. RESULTS: Among the 18 participants (mean age, 64 years), 83% were female, most (89%) had received surgery, and 56% received chemotherapy. Most participants viewed DFS as an intrinsically meaningful treatment outcome, for reasons such as alignment with treatment goals, and the perception that DFS would help maintain a high quality of life. One individual was interested in DFS only as a potential surrogate for overall survival. Participants desired access to new treatments that improve DFS and emphasized this within the context of promoting patient agency in treatment decision making. CONCLUSIONS: These findings suggest DFS is a meaningful endpoint from the perspective of survivors of lung cancer; and may help inform decisions regarding regulatory approval and reimbursement of new treatments based on DFS data.

A descriptive analysis of blood mercury test results in British Columbia to identify excessive exposures.

OBJECTIVE: The objective of this study was to describe who in British Columbia (BC) is tested for blood mercury, the distribution of their results, and the adequacy of follow-up testing. METHODS: The BC Centre for Disease Control (BCCDC) obtained records of clinician-ordered analyses of blood mercury conducted by BC laboratories during 2009 and 2010. We conducted a descriptive analysis with statistical testing of who was tested, the distribution of their blood mercury concentrations, whose results exceeded Health Canada's proposed guidance values (8 µg/L (40 nmol/L) for children/adolescents ≤ 18 years and women 19-49 years, and 20 µg/L (100 nmol/L) for other adults), and patterns of repeat testing. RESULTS: Mercury test results for 6487 individuals were reviewed. Adults ≥ 50 years had the highest testing rates. The median blood mercury concentration for all tested persons was 1.8 µg/L. Nine percent of women aged 19-49 years had results exceeding Health Canada's provisional guidance value of 8 µg/L. Data from one of BC's two biomarker laboratories indicated that some residents of Vancouver and nearby suburbs have higher exposure to mercury than other BC residents. Of 127 individuals who had results in 2009 exceeding provisional guidance values, only 45% were tested again within 12 months. CONCLUSION: Collating and analyzing all clinical biomarker testing such as blood mercury at a provincial population level allows for assessment of the adequacy and appropriateness of follow-up testing and suggests which regional and demographic strata are at higher levels of exposure.

RéSUMé: OBJECTIF: Décrire qui, en Colombie-Britannique (C.-B.), fait l'objet de dosages du mercure sanguin, quelle est la distribution des résultats, et si les dosages de suivi sont adéquats. MéTHODE: Le BC Centre for Disease Control (BCCDC) a obtenu les dossiers de dosages du mercure sanguin demandés par les cliniciens et effectués par les laboratoires de la province en 2009 et 2010. Nous avons effectué une analyse descriptive avec des contrôles statistiques des personnes testées, de la distribution de leurs concentrations de mercure sanguin, des sujets dont les résultats dépassaient les valeurs provisoires indiquées par Santé Canada (8 µg/L [40 nmol/L] pour les enfants/adolescents de ≤ 18 ans et les femmes de 19-49 ans et 20 µg/L [100 nmol/L] pour les autres adultes) et des tendances des dosages ultérieurs. RéSULTATS: Les résultats des dosages du mercure de 6 487 personnes ont été examinés. Les taux de dosage les plus élevés ont été observés chez les adultes de ≥ 50 ans. La concentration médiane de mercure sanguin chez toutes les personnes testées était de 1,8 µg/L. Neuf p. cent des femmes de 19 à 49 ans présentaient des résultats supérieurs à la valeur provisoire de 8 µg/L indiquée par Santé Canada. Selon les données de l'un des deux laboratoires de biomarqueurs de la C.-B., l'exposition au mercure de certains résidents de Vancouver et des banlieues proches était supérieure à celle des autres résidents de la province. Sur les 127 personnes dont les résultats en 2009 dépassaient les valeurs provisoires indiquées, 45 % seulement ont fait l'objet d'un nouveau dosage dans un délai de 12 mois. CONCLUSION: La collecte et l'analyse de tous les essais cliniques sur les biomarqueurs comme le mercure sanguin à l'échelle d'une population provinciale permettent de déterminer l'adéquation et la pertinence des dosages de suivi et indiquent dans quelles strates régionales et démographiques les niveaux d'exposition sont les plus élevés.

Electronic cigarette exposures reported to the British Columbia Drug and Poison Information Centre: an observational case series.

BACKGROUND: Electronic nicotine delivery systems (ENDSs), including electronic cigarettes (e-cigarettes), are rapidly gaining popularity. The aim of this study was to use poison centre data to describe epidemiological trends in ENDS-related exposures. METHODS: We conducted an observational case series study using records containing both coded fields and free-text narratives from the British Columbia Drug and Poison Information Centre for all calls involving exposure to ENDS received from 2012 to 2017. We described trends in exposures and exposed people, as well as clinical effects. RESULTS: A total of 243 calls were recorded for 186 unique exposures to ENDS devices, e-juice, e-cigarette cartridges and other associated paraphernalia over the study period. Calls related to ENDS exposures increased nearly sixfold between 2013 and 2014 and did not decline subsequently. Exposures were most frequently documented in children aged 4 years or less (81 [43.5%]), with 58 (31.0%) in 1- and 2-year-olds. Seventy-two exposures (89%) in children aged 4 years or less were due to accidental ingestion, whereas adults aged 25 years or more called the poison centre following ENDS malfunctions (7 [23%], spills (4 [13%]) and exposure to e-juice mistaken for other substances (4 [13%]). Of the 186 exposed people, 87 (46.8%) reported symptoms. INTERPRETATION: British Columbia experienced a sixfold increase in ENDS-related calls to the provincial poison centre between 2012 and 2017, driven by ingestions in young children. Regulatory approaches aimed at minimizing children's access to ENDS, clear labelling of nicotine concentration, and packaging that reduces the likelihood of spills, product confusion and malfunction should be considered.