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Singh B.N.,Veterans Administration Greater Los Angeles Healthcare System
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2010

In recent years, a major development in the treatment of atrial fibrillation (AF) is the use of catheter ablation, and a significant number of patients may benefit from this mode of therapy. On a global scale, it may not be feasible to deal with most patients solely on the basis of ablation. Therefore, it is likely that much of the therapy for AF will continue to rely on antiarrhythmic agents for maintaining sinus rhythm. For many years, amiodarone and sotalol have been the dominant antiarrhythmic agents, with amiodarone being the most effective antiarrhythmic in suppressing AF; however, amiodarone use is limited due to concerns of end-organ toxicity. Upstream therapies, such as statins, fish oil, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers may also provide additive efficacy to these and other membrane-active antiarrhythmics. In recent years, a number of new agents are being developed and the first successful congener of amiodarone, dronedarone, has been shown to be effective in controlling AF and reducing cardiovascular hospitalization. This paper explores the possibility of augmenting the extent of controlling AF by combining multiple potent antiarrhythmic agents old and new. © The Author(s) 2010.


Potter R.M.,Molecular Therapeutics | Harikumar K.G.,Molecular Therapeutics | Wu S.V.,Veterans Administration Greater Los Angeles Healthcare System | Miller L.J.,Molecular Therapeutics
Journal of Lipid Research | Year: 2012

Recent studies indicate that membrane cholesterol can associate with G protein-coupled receptors (GPCRs) and affect their function. Previously, we reported that manipulation of membrane cholesterol affects ligand binding and signal transduction of the type 1 cholecystokinin receptor (CCK1R), a Class A GPCR. We now demonstrate that the closely related type 2 cholecystokinin receptor (CCK2R) does not share this cholesterol sensitivity. The sequences of both receptors reveal almost identical cholesterol interaction motifs in analogous locations in transmembrane segments two, three, four, and five. The disparity in cholesterol sensitivity between these receptors, despite their close structural relationship, provides a unique opportunity to define the possible structural basis of cholesterol sensitivity of CCK1R. To evaluate the relative contributions of different regions of CCK1R to cholesterol sensitivity, we performed ligand binding studies and biological activity assays of wildtype and CCK2R/CCK1R chimeric receptor-bearing Chinese hamster ovary cells after manipulation of membrane cholesterol. We also extended these studies to site-directed mutations within the cholesterol interaction motifs. The results contribute to a better understanding of the structural requirements for cholesterol sensitivity in CCK1R and provides insight into the function of other cholesterol-sensitive Class A GPCRs.


Puppin C.,University of Udine | Passon N.,University of Udine | Hershman J.M.,Veterans Administration Greater Los Angeles Healthcare System | Filetti S.,University of Rome La Sapienza | And 4 more authors.
Journal of Molecular Endocrinology | Year: 2012

Histone deacetylase inhibitors (HDACi) have shown both anti-proliferative and redifferentiating effects in thyroid cancer cells. Also, they induce the expression of the sodium-iodide symporter gene (NIS (SLC5A5)), a crucial step for radioiodine treatment of thyroid malignancies. Here we investigated the effects of suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) on BCPAP and FRO thyroid cancer cells, extending our analysis on the epigenetic mechanisms underlying the NIS gene expression stimulation. In both cell lines we found a cooperative effect of the two compounds on either cell viability and NIS gene expression, resulting in acquired/increased ability to uptake the radioiodine. Such effect was specific since it was not observed for expression of other genes or when SAHA was used in combination with trichostatin A. By using chromatin immunoprecipitation, we investigated epigenetic mechanisms underlying SAHA and VPA effects. Cooperation among the two HDACi occurred on H3 histone trimethylation at lysine 4 (H3K4me3) and not on histone acetylation. However, effects on H3K4me3 were detected only at the level of NIS Proximal Basal Promoter (NIS-PBP) in FRO cells and only at the level of NIS Upstream Enhancer (NIS-NUE) in BCPAP cells. Our data indicate that epigenetic changes are involved in the synergistic effects of VPA and SAHA on NIS gene expression and that the cellular context modifies effects of HDACi in terms of H3K4me3 target sequence. Investigation of cooperation among different HDACi may provide clues for better defining their mechanism of action in view of their use in thyroid cancer treatment. © 2012 Society for Endocrinology.


Cingolani E.,Cedars Sinai Medical Center | Lepor N.E.,Cedars Sinai Medical Center | Singh B.N.,Veterans Administration Greater Los Angeles Healthcare System
Reviews in Cardiovascular Medicine | Year: 2011

Ranolazine, a newer anti-ischemic agent that appears to induce a more efficient utilization of adenosine triphosphate at the cellular level, has been shown to be clinically beneficial in patients with chronic stable angina. More recently, the antiarrhythmic effects of the drug have been described in patients with acute coronary syndromes, as well as in those with atrial fibrillation, when combined with other agents. Experimentally, the predominant inhibitory effects on late I Na, I Ca, I Na-Ca, and I Ks, with little or no effect on I to or I K1, have been demonstrated. Different experimental models have shown the potential beneficial effect of the drug in both supraventricular and ventricular arrhythmias. Interestingly, despite its potential prolongation of the QT interval, ranolazine does not appear to induce ventricular arrhythmias in animal models. Whether the antiarrhythmic effect is secondary to a more efficient energy production by the cardiac cell or by its direct effect on ion channels is still unclear. The effect of ranolazine on other ionic currents, as well as its potential as a clinically relevant antiarrhythmic agent, still needs to be studied. © 2011 MedReviews®, LLC.


Cordell C.B.,Alzheimers Association | Borson S.,University of Washington | Boustani M.,Indiana University | Boustani M.,Regenstrief Institute Inc. | And 6 more authors.
Alzheimer's and Dementia | Year: 2013

The Patient Protection and Affordable Care Act added a new Medicare benefit, the Annual Wellness Visit (AWV), effective January 1, 2011. The AWV requires an assessment to detect cognitive impairment. The Centers for Medicare and Medicaid Services (CMS) elected not to recommend a specific assessment tool because there is no single, universally accepted screen that satisfies all needs in the detection of cognitive impairment. To provide primary care physicians with guidance on cognitive assessment during the AWV, and when referral or further testing is needed, the Alzheimer's Association convened a group of experts to develop recommendations. The resulting Alzheimer's Association Medicare Annual Wellness Visit Algorithm for Assessment of Cognition includes review of patient Health Risk Assessment (HRA) information, patient observation, unstructured queries during the AWV, and use of structured cognitive assessment tools for both patients and informants. Widespread implementation of this algorithm could be the first step in reducing the prevalence of missed or delayed dementia diagnosis, thus allowing for better healthcare management and more favorable outcomes for affected patients and their families and caregivers. © 2013 The Alzheimer's Association. All rights reserved.

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