A scoping review of qualitative research on barriers and facilitators to the use of supervised consumption services.

A substantial body of evidence demonstrates that supervised consumption services (SCS) mitigate a variety of drug-related harms, including decreasing overdose deaths, infectious disease transmission, and connecting people who use drugs (PWUD) to various health and social services. Research on SCS has predominantly been quantitative, though qualitative research on these services has increased substantially over the last decade. Qualitative methods provide a framework for developing a richer and more nuanced understanding of meanings and contexts associated with drug use, health service implementation, and experience. We present findings from a scoping review of qualitative studies on experiences of PWUD with SCS published between 1997 and 2022. In total, forty-two papers were included in this analysis. Four primary themes emerged from our analysis: 1) Influence of SCS on health and wellbeing among PWUD, 2) the physical environment of SCS can be both a facilitator and barrier to use, 3) social resources can shape and reshape the context within which PWUD benefit from SCS, and 4) various intersecting forces at play both support and harm PWUD in relation to their experiences with SCS. We discuss the primary facilitators and barriers of SCS use and conclude with suggestions to inform future qualitative research, SCS implementation, and PWUD-centered approaches to drug policy.

A fluvial mercury budget for Lake Ontario.

Watershed mercury (Hg) flux was calculated for ten inflowing rivers and the outlet for Lake Ontario using empirical measurements from two independent field-sampling programs. Total Hg (THg) flux for nine study watersheds that directly drain into the lake ranged from 0.2 kg/yr to 13 kg/yr, with the dominant fluvial THg load from the Niagara River at 154 kg/yr. THg loss at the outlet (St. Lawrence River) was 68 kg/yr and has declined approximately 40% over the past decade. Fluvial Hg inputs largely (62%) occur in the dissolved fraction and are similar to estimates of atmospheric Hg inputs. Fluvial mass balances suggest strong in-lake retention of particulate Hg inputs (99%), compared to dissolved total Hg (45%) and methyl Hg (22%) fractions. Wetland land cover is a good predictor of methyl Hg yield for Lake Ontario watersheds. Sediment deposition studies, coupled atmospheric and fluvial Hg fluxes, and a comparison of this work with previous measurements indicate that Lake Ontario is a net sink of Hg inputs and not at steady state likely because of recent decreases in point source inputs and atmospheric Hg deposition.

Amlodipine prevents apoptotic cell death by correction of elevated intracellular calcium in a primary neuronal model of Batten disease (CLN3 disease).

CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease) is a severe pediatric neurodegenerative disorder for which there is currently no effective treatment. The disease is characterized by progressive neuronal death, which may be triggered by abnormal intracellular calcium levels leading to neuronal apoptosis. Previously, we demonstrated reversal of the calcium effect in a neuroblastoma cell line using amlodipine and other calcium channel antagonists. In the present studies, we developed a CLN3 siRNA-inhibited primary rat neuron model to further study etoposide-induced calcium changes and apoptosis in CLN3 disease followed by recovery experiments with amlodipine. Our results show that intracellular calcium is significantly elevated in siRNA-inhibited cortical neurons after potassium chloride-induced depolarization. We were also able to show that amlodipine, a predominantly L-type dihydropyrimidine calcium channel antagonist can reverse the aberrant calcium elevations in this model of the disease. We performed an in situ TUNEL assay following etoposide-exposure to siRNA inhibited primary neurons, and apoptotic nuclei were detected providing additional evidence that increased neuronal apoptosis is associated with increased calcium levels. Amlodipine also reduced the absolute number of apoptotic cells in this experimental model.

Screening for calcium channel modulators in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells reveals a significant decrease of intracellular calcium levels by selected L-type calcium channel blockers.

BACKGROUND: Defects of the CLN3 gene on chromosome 16p12.1 lead to the juvenile form of neuronal ceroid-lipofuscinosis (JNCL, Batten Disease), the most common recessive inherited neurodegenerative disorder in children. Dysregulation of intracellular calcium homeostasis in the absence of a functional CLN3 protein (CLN3P, Battenin) has been linked to synaptic dysfunction and accelerated apoptosis in vulnerable neuronal cells. Prolonged increase of intracellular calcium concentration is considered to be a significant trigger for neuronal apoptosis and cellular loss in JNCL. METHODS: We examined the potential effect of 41 different calcium channel modulators on intracellular calcium concentration in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells. RESULTS: Six drugs belonging to the group of voltage dependent L-type channel blockers show significant lowering of the increased intracellular calcium levels in CLN3 siRNA knock down cells. CONCLUSIONS: Our studies provide important new data suggesting possible beneficial effects of the tested drugs on calcium flux regulated pathways in neuronal cell death. Therapeutic intervention in this untreatable disease will likely require drugs that cross the blood-brain barrier as did all of the positively screened drugs in this study. GENERAL SIGNIFICANCE: Better comprehension of the mechanism of neurodegeneration in rare recessive disorders, such as neuronal ceroid-lipofuscinoses, is likely to help to better understand mechanisms involved in more complex genetic neurodegenerative conditions, such as those associated with aging.