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CONCLUSIONS GGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.BACKGROUND Youth and young adults frequently use social media and are susceptible to tobacco use. This study is the first to provide a systematic overview of how leading tobacco product brands use popular social media platforms. METHODS We identified 112 leading brands of e-cigarettes, hookah, cigars, cigarettes and smokeless tobacco based on sales and self-report user data. We searched for each brand on six platforms Instagram, Facebook, Twitter, YouTube, Pinterest and Tumblr. In early 2019, we conducted a content analysis of each page, coding age restrictions, warning display, page characteristics and post characteristics. RESULTS Cigarette brands were generally not present. Most e-cigarettes, hookah and cigar brands had pages on at least two platforms. One-third of smokeless brands had pages on at least one platform. Few brands had pages on Pinterest and Tumblr. Most pages had existed for 3-5 years. Overall, brand pages rarely used age gating, did not display health warnings, generally posted images of a product alone and often used hashtags unrelated to tobacco. Brands commonly used special features like ephemeral posts on Instagram and pop-up chat windows on Facebook. Many pages displayed images of young people and mentioned flavour. Median followers per brand ranged from about 1 000-10 000, and total followers summed across brands reached over 5 million on Facebook and Instagram alone. CONCLUSIONS Leading brands of most tobacco product types use social media extensively. Several findings identify issues related to youth exposure to and appeal of tobacco social media marketing. Findings can inform tobacco education efforts and regulation. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.An orally available and novel small molecule, ONO-7579 (N-2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea), is a highly potent and selective pan-tropomyosin receptor kinase (TRK) inhibitor. The objective of the present study was to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and antitumor efficacy relationships of ONO-7579 in mice xenografted with a human colorectal cancer cell line, KM12 (harboring the TPM3-NTRK1 fusion gene), via a PK/PD modeling approach. Plasma and tumor concentrations of ONO-7579, tumor levels of phosphorylated TPM3-TRKA (pTRKA), and tumor volumes in the murine model were measured with a single or multiple dose of ONO-7579 0.06-0.60 mg/kg administered once daily. The PK/PD/efficacy models were developed in a sequential manner. Changes in plasma concentrations of ONO-7579 were described with an oral one-compartment model. Tumor concentrations of ONO-7579 were higher than plasma concentrations, and changes for explaining the antitumor efficacy of TRK inhibitors using a PK/PD modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 , a novel pan-TRK inhibitor. The American Society for Pharmacology and Experimental Therapeutics.Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have become a promising cell source for cardiovascular research. see more The electrophysiological characteristic of hESC-CMs has been generally studied, but little is known about electrophysiological response to adrenergic adrenoreceptor (AR) activation. This study aims to characterize electrophysiological responses of hESC-CMs to adrenergic stimulation, in terms of the conduction velocity (CV) and action potential (AP) shape. The H9 hESC-CMs were acquired by a classical differentiation protocol and cultured to achieve confluent cell monolayers. The AP shape and CV among the monolayers were recorded using optical mapping during electrophysiological and pharmacological stimulation experiments. RT-qPCR and Western blot were adopted to determine the expression levels of connexin and ion channel gene and protein. Chronic β-AR stimulation by isoproterenol for 24h in hESC-CMs monolayers increased CV by approximately 50%, while a-AR or acute β-AR stimulation had noncise signaling pathway in the ARs regulation of action potential shape and electrical propagation across hESCs-CMs monolayer. It is β1-AR, not β2-AR contributing to the modification of conduction velocity in hESC-CMs and accelerates conduction velocity by up-regulating Cx43 via PKA/MEK/MAPK pathway. The American Society for Pharmacology and Experimental Therapeutics.Loss-of-function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to isoform-selectively activate specific Kv channels. One example is KCNA1 (Kv1.1), an archetypal Shaker-type Kv channel, loss-of-function mutations in which cause Episodic Ataxia Type 1 (EA1). EA1 causes constant myokomia, episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and modified versions of glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of fluorine atoms within the fluorophenyl ring of glycine derivatives produces isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1.