Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

Mutations in the neuron-specific α3 isoform of the Na+/K+-ATPase are found in patients suffering from Rapid onset Dystonia Parkinsonism and Alternating Hemiplegia of Childhood, two closely related movement disorders. We show that mice harboring a heterozygous hot spot disease mutation, D801Y (α3+/D801Y), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α3+/D801Y mice revealed irregular firing of Purkinje cells and their synaptic targets, the deep cerebellar nuclei neurons, which was further exacerbated during dystonia and evolved into abnormal high-frequency burst-like firing. Biophysically, we show that the D-to-Y mutation abolished pump-mediated Na+/K+ exchange, but allowed the pumps to bind Na+ and become phosphorylated. These findings implicate aberrant cerebellar activity in α3 isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3 isoform Na+/K+-ATPase

The impact of opioid treatment on regional gastrointestinal transit

Abstract Aims To employ a human experimental model of opioid-induced bowel dysfunction (OIBD) in healthy volunteers, and evaluate the impact of opioid treatment compared to placebo on gastrointestinal (GI) symptoms and motility, assessed by questionnaires and regional GI transit times. Methods Twenty-five healthy males were randomly assigned to oxycodone or placebo for five days in a double-blind, crossover design. Adverse GI effects were measured with bowel function index, gastrointestinal symptom rating scale, patient assessment of constipation symptoms questionnaire, and bristol stool form scale. Regional GI transit times were determined using the 3D-Transit system and segmental colonic transit times were determined using a custom Matlab® graphical user interface. Results GI symptom scores increased significantly across all applied questionnaires during opioid treatment. Oxycodone increased median total GI transit time from 22.2 to 43.9 h (P&lt; 0.01), segmental transit times in the cecum and ascending colon from 5.7 to 9.9 h (P&lt;0.05), rectosigmoid transit time from 2.7 to 9.0 h (P&lt;0.05), and colorectal transit time from 18.6 to 38.6 h (P&lt;0.01). No association between questionnaire scores and segmental transit times were detected. Conclusions Self-assessed adverse GI effects and increased GI transit times in different segments were induced during oxycodone treatment. This detailed information about segmental changes in motility has great potential for future interventional head-to-head trials of different laxative regimes for prevention and treatment of OIBD. </jats:sec