Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that ...prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms.
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Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 ...and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes. In cells, A-196 induced a global decrease in H4K20me2 and H4K20me3 and a concomitant increase in H4K20me1. A-196 inhibited 53BP1 foci formation upon ionizing radiation and reduced NHEJ-mediated DNA-break repair but did not affect homology-directed repair. These results demonstrate the role of SUV4-20 enzymatic activity in H4K20 methylation and DNA repair. A-196 represents a first-in-class chemical probe of SUV4-20 to investigate the role of histone methyltransferases in genomic integrity.
The mainstream smoke yields of 14 polycyclic aromatic hydrocarbons (PAHs) were determined for 50 commercial U.S. cigarettes using a validated GC/MS method with the International Organization of ...Standardization (ISO) and Canadian Intense (CI) smoking machine regimens. PAH mainstream smoke deliveries vary widely among the commercial cigarettes with the ISO smoking regimen primarily because of differing filter ventilation. The more abundant, lower molecular weight PAHs such as naphthalene, fluorene, and phenanthrene predominantly comprise the total PAH yields. In contrast, delivery yields of high molecular weight PAHs such as benzobfluoranthene, benzoepyrene, benzokfluoranthene, and benzoapyrene (BaP) are much lower. Comparative analysis of PAHs deliveries shows brand specific differences. Correlation analysis shows strong positive associations between BaP and most of the other PAHs as well as total PAHs. The results suggest that BaP may be a representative marker for other PAH constituents in cigarette smoke generated from similarly blended tobacco, particularly those PAHs with similar molecular weights and chemical structures.
To review current information about diagnosis and management of tinnitus aiming to identify opportunities for achieving a cost-effective, efficient, evidence-based approach that meets the needs of ...tinnitus sufferers.
PubMed/MEDLINE.
In total, 249 relevant published reports were reviewed. Pertinent keywords and MeSH terms identified reports via PubMed and EMBASE. Acknowledged experts were consulted on ways to improve tinnitus management.
There may be opportunities to improve evaluation and management of patients with tinnitus using modern modes of communication and a multidisciplinary therapeutic approach.
Tinnitus can adversely affect quality of life while being time-consuming and costly to evaluate and manage. Based on both personal experience and the reports of others, patients with tinnitus who choose to see a physician primarily want to know two things: (1) that the tinnitus that is so distressing will not remain at the same level of severity forever and (2) that something can be done to help cope with the tinnitus that is so annoying. Recent advancements in internet communications, social media, information technology, artificial intelligence, machine learning, holistic medical care, mind-body integrative health care, and multidisciplinary approaches in medical therapeutics may be possibly making new ways of meeting the needs of patients with tinnitus.
The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is ...the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of
RNAs, which are noncoding transcripts of a human retrotransposon.
RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces
RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.
Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly ...understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer.
Our study estimates the sensitivity and specificity of Medicare claims to identify clinically-diagnosed dementia, and documents how errors in dementia assessment affect dementia cost estimates. We ...compared Medicare claims from 1993-2005 to clinical dementia assessments carried out in 2001-2003 for the Aging Demographics and Memory Study (ADAMS) cohort (n = 758) of the Health and Retirement Study. The sensitivity and specificity of Medicare claims was 0.85 and 0.89 for dementia (0.64 and 0.95 for AD). Persons with dementia cost the Medicare program (in 2003) $7,135 more than controls (P < 0.001) when using claims to identify dementia, compared to $5,684 more when using ADAMS (P < 0.001). Using Medicare claims to identify dementia results in a 110% increase in costs for those with dementia as compared to a 68% increase when using ADAMS to identify disease, net of other variables. Persons with false positive Medicare claims notations of dementia were the most expensive group of subjects ($11,294 versus $4,065, for true negatives P < 0.001). Medicare claims overcount the true prevalence of dementia, but there are both false positive and negative assessments of disease. The use of Medicare claims to identify dementia results in an overstatement of the increase in Medicare costs that are due to dementia.
Background: Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease ...mitochondrial oxidative damage may improve outcome. The mitochondria‐targeted anti‐oxidant mitoquinone combines a potent anti‐oxidant with a lipophilic cation that causes it to accumulate several‐hundred fold within mitochondria in vivo.
Aims: In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV‐infected patients.
Methods: Thirty HCV patients who were either non‐responders or unsuitable candidates for standard‐of‐care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured.
Results: Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment.
Conclusions: Administration of the mitochondria‐targeted anti‐oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria‐targeted anti‐oxidants in HCV and other liver diseases are warranted.
This study examined the variation of benzoapyrene (BaP), N′-nitrosonornicotine (NNN), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) levels in 16 smokeless tobacco products from several ...different product subcategories obtained at two different locations and at two different procurement times. BaP quantities range from 0.6 to 160 ng/g on a wet-weight basis, whereas NNN and NNK quantities range from 276 to 10473 ng/g and 79 to 28882 ng/g, respectively. The BaP, NNN, and NNK quantities vary widely among various smokeless tobacco product categories and among various brands within each product subcategory. Dry snuff products contain the highest BaP, NNN, and NNK quantities, whereas loose and portioned snus products contain the lowest BaP, NNN, and NNK levels. In general, variation of BaP, NNN, and NNK levels across four sets of each product brand purchased six months apart and at two different locations show statistically significant differences (p < 0.05), although with a much narrower product set-to-set variability.
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