Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.

Clinical factors associated with successful embolization of lower gastrointestinal bleeding.

AIM: To develop a model of clinical factors that may predict: (1) technically and clinically successful embolization of a bleeding vessel at digital subtraction angiography (DSA) for lower gastrointestinal bleed (LGIB); (2) a negative DSA in the presence of positive CT-mesenteric angiography (CTMA) for LGIB. METHODS: A retrospective cohort study of all DSAs conducted with intent for embolization for acute LGIB over a 10-year period was undertaken. Pre-procedural and intra-procedural clinical variables were evaluated using uni- and multi-variate analysis. RESULTS: One hundred and twenty-three DSAs were evaluated. Technical success was 81% and clinical success 78% where DSA was positive. Technical success was associated with super-selective approach, contrast extravasation on CT, haemoglobin drop, anatomical source and time from CT to DSA on univariate analysis. On multivariate analysis, time from CT to DSA was significant with a higher success probability within 120 min with different factors being salient depending on degree of delay. Clinical success was only associated with activated partial thromboplastin time (<27.5 s). A negative DSA was associated with anatomical source, haemodynamic stability, platelet count and time from CT to DSA on univariate analysis. The latter three remained so on multivariate analysis. CONCLUSION: A triaging approach to utilizing emergency DSA may be helpful. If prolonged delay between CT and DSA is anticipated, with haemodynamic stability and a near-normal platelet count, the DSA may not be fruitful. Technical success may be more likely if DSA occurs within 120 min. Clinical success may be more likely if activated partial thromboplastin time is within normal range.