Screening for atrial fibrillation in care homes using pulse palpation and the AliveCor Kardia Mobile® device: a comparative cross-sectional pilot study.

BACKGROUND: Atrial fibrillation (AF) is a major cause of stroke in older people. Exacerbated by age and co-morbidities, residents of care homes are more likely to develop AF and less likely to receive oral anticoagulants. AIM: To determine the prevalence of AF using the design and methodology of the Pharmacists Detecting Atrial Fibrillation (PDAF) study in a care home setting. METHOD: A cross-sectional AF screening pilot study within four UK care homes, three residential and one residential/nursing. Screening followed the original PDAF protocol: a manual pulse check, followed by a single-Lead ECG (SLECG, AliveCor Kardia Mobile (KMD)) delivered by a pharmacist. All recorded SLECG were reviewed by a cardiologist and any residents requiring follow-up investigations were referred to their general practitioner. RESULTS: Fifty-three of 112 care home residents participated. From 52 SLECGs recorded, the cardiologist interpreted 13.5% (7/52) as having possible AF of which 9.6% (5/52) were previously unknown. One resident with previously unknown AF received anticoagulation. CONCLUSION: This study has shown a need for AF screening in care homes and that elements of the PDAF screening protocol are transferable in this setting. Early diagnosis and treatment of AF are essential to reduce the risk of stroke in this population.

Aprepitant is a novel, selective activator of the K2P channel TRAAK.

TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of ∼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels.

Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide.

BACKGROUND AND PURPOSE: The TASK subfamily of two pore domain potassium channels (K2P) encodes for leak K currents, contributing to the resting membrane potential of many neurons and regulating their excitability. TASK1 and TASK3 channels are regulated by a number of pharmacological and physiological mediators including cannabinoids such as methanandamide. In this study, we investigate how methanandamide blocks these channels. EXPERIMENTAL APPROACH: Currents through wild type and mutated TASK1 and TASK3 channels expressed in modified HEK-293 cells were measured using whole-cell electrophysiological recordings in the presence and absence of methanandamide. KEY RESULTS: Methanandamide (3 microM) produced substantial block of hTASK1, hTASK3 and mTASK3 channels but was most potent at blocking hTASK3 channels. Block of these channels was irreversible unless cells were washed with buffer containing bovine serum albumin. Mutation of the distal six amino acids of TASK1 did not alter methanandamide inhibition, whilst C terminal truncation of TASK3 channels caused a small but significant reduction of inhibition. However, deletion of six amino acids (VLRFLT) at the interface between the final transmembrane domain and cytoplasmic C terminus of TASK3 channels gave functional currents that were no longer inhibited by methanandamide or by activation of GPCRs. CONCLUSIONS AND IMPLICATIONS: Methanandamide potently blocked TASK3 and TASK1 channels and both methanandamide and G protein-mediated inhibition converged on the same intracellular gating pathway. Physiologically, methanandamide block of TASK1 and TASK3 channels may underpin a number of CNS effects of cannabinoids that are not mediated through activation of CB1 or CB2 receptors.

Neuronal ion channels and their sensitivity to extremely low frequency weak electric field effects.

Neuronal ion channels are gated pores whose opening and closing is usually regulated by factors such as voltage or ligands. They are often selectively permeable to ions such as sodium, potassium or calcium. Rapid signalling in neurons requires fast voltage sensitive mechanisms for closing and opening the pore. Anything that interferes with the membrane voltage can alter channel gating and comparatively small changes in the gating properties of a channel can have profound effects. Extremely low frequency electrical or magnetic fields are thought to produce, at most, microvolt changes in neuronal membrane potential. At first sight, such changes in membrane potential seem orders of magnitude too small to significantly influence neuronal signalling. However, in the central nervous system, a number of mechanisms exist which amplify signals. This may allow such small changes in membrane potential to induce significant physiological effects.

The sfr6 mutation in Arabidopsis suppresses low-temperature induction of genes dependent on the CRT/DRE sequence motif.

The sfr mutations, which result in sensitivity to freezing after cold acclimation, define genes that are required for freezing tolerance. We tested plants homozygous for mutations sfr2 to sfr7 for cold-induced gene expression and found that sfr 6 plants were deficient in cold-inducible expression of the genes KIN1, COR15a, and LTI78, which all contain the C repeat/dehydration-responsive element (CRT/DRE) motif in their promoters. Similarly, sfr 6 plants failed to induce KIN1 normally in response to either osmotic stress or the application of abscisic acid. In contrast, cold-inducible expression of genes CBF1, CBF2, CBF3, and ATP5CS1, which lack the CRT/DRE motif, was not affected. The freezing-sensitive phenotype that defines sfr 6 also was found to be tightly linked to the gene expression phenotype. To determine whether the failure of cold induction of CRT/DRE-containing genes in sfr 6 was due to altered low-temperature calcium signaling, cold-induced cytosolic-free calcium ([Ca2+]cyt) elevations were investigated in the sfr 6 mutant, but these were found to be indistinguishable from those of the wild type. We discuss the possibilities that CRT/DRE binding proteins (such as CBF1) require activation to play a role in transcription and that the SFR6 protein is a vital component of their activation.