DYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.
RATIONALE: To compare the rate, triggers and management of anaphylaxis between adult emergency departments (ED) in Western and Eastern Canada. METHODS: As part of the Cross-Canada Anaphylaxis Registry (C-CARE), we conducted a chart review of adults presenting with allergyrelated ICD-10 codes to a tertiary care centre ED in Western Canada (Edmonton, Alberta) between March 1, 2011 and February 28, 2012. Anaphylaxis cases were defined as those that fulfilled the published consensus definition for anaphylaxis. Clinical and management data were collected and compared to published data from an ED in Eastern Canada (Montreal, Quebec). RESULTS: Among 59,195 presentations to the Edmonton ED, 0.22% (95% CI 0.19%, 0.27%) were due to anaphylaxis. Food was the trigger in 57.1% (48.3%, 65.7%), mainly tree nut (21.0% (12.5%, 31.9%) of foodtriggered cases). Epinephrine was used in 54.9% (46.0%, 63.5%) and 41.3% (32.9%, 50.2%) were prescribed an auto-injector. In Montreal, 0.26% (0.21%, 0.32%) of ED presentations were due to anaphylaxis, and 63.3% (52.9%, 72.6%) were triggered by food, primarily shellfish (12.9% (6.1%, 24.4%) of food-triggered cases). Epinephrine was used to treat 49.0% (38.8%, 59.2%) of patients and 67.1% (55.3%, 77.2%) were prescribed an auto-injector. CONCLUSIONS: In Western and Eastern Canada, anaphylaxis accounted for over 0.2% of adult ED visits and was mainly due to foods. Tree nuts rather than shellfish were the main food triggers in Western Canada. Given the poor adherence to guidelines stipulating epinephrine use in all anaphylaxis cases, education programs promoting early epinephrine use are required across the country.
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