Statin-Associated Muscular and Renal Adverse Events: Data Mining of the Public Version of the FDA Adverse Event Reporting System

OBJECTIVE: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank-order of the association. METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. RESULTS: Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non-acute renal failure or for an increase in blood creatinine level. CONCLUSIONS: Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin-associated adverse events

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40. DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials

Intrinsic Determinants of Aβ12–24 pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies

The propensity of amyloid- (A) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, -sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A amyloid formation; it is highly prompted in the order of pH 5.02.98.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of -sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases

Deep-Sea Origin and In-Situ Diversification of Chrysogorgiid Octocorals

The diversity, ubiquity and prevalence in deep waters of the octocoral family Chrysogorgiidae Verrill, 1883 make it noteworthy as a model system to study radiation and diversification in the deep sea. Here we provide the first comprehensive phylogenetic analysis of the Chrysogorgiidae, and compare phylogeny and depth distribution. Phylogenetic relationships among 10 of 14 currently-described Chrysogorgiidae genera were inferred based on mitochondrial (mtMutS, cox1) and nuclear (18S) markers. Bathymetric distribution was estimated from multiple sources, including museum records, a literature review, and our own sampling records (985 stations, 2345 specimens). Genetic analyses suggest that the Chrysogorgiidae as currently described is a polyphyletic family. Shallow-water genera, and two of eight deep-water genera, appear more closely related to other octocoral families than to the remainder of the monophyletic, deep-water chrysogorgiid genera. Monophyletic chrysogorgiids are composed of strictly (Iridogorgia Verrill, 1883, Metallogorgia Versluys, 1902, Radicipes Stearns, 1883, Pseudochrysogorgia Pante & France, 2010) and predominantly (Chrysogorgia Duchassaing & Michelotti, 1864) deep-sea genera that diversified in situ. This group is sister to gold corals (Primnoidae Milne Edwards, 1857) and deep-sea bamboo corals (Keratoisidinae Gray, 1870), whose diversity also peaks in the deep sea. Nine species of Chrysogorgia that were described from depths shallower than 200 m, and mtMutS haplotypes sequenced from specimens sampled as shallow as 101 m, suggest a shallow-water emergence of some Chrysogorgia species

The role of morphine in regulation of cancer cell growth

Morphine is considered the “gold standard” for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells

Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes

Alzheimer’s disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β − and γ − secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer’s disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0129-7) contains supplementary material, which is available to authorized users

The DUNE Far Detector Interim Design Report, Volume 3: Dual-Phase Module

The DUNE IDR describes the proposed physics program and technical designs of the DUNE far detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 3 describes the dual-phase module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure

The DUNE Far Detector Interim Design Report, Volume 2: Single-Phase Module

The DUNE IDR describes the proposed physics program and technical designs of the DUNE far detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 2 describes the single-phase module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure

The DUNE Far Detector Interim Design Report Volume 1: Physics, Technology and Strategies

The DUNE IDR describes the proposed physics program and technical designs of the DUNE Far Detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 1 contains an executive summary that describes the general aims of this document. The remainder of this first volume provides a more detailed description of the DUNE physics program that drives the choice of detector technologies. It also includes concise outlines of two overarching systems that have not yet evolved to consortium structures: computing and calibration. Volumes 2 and 3 of this IDR describe, for the single-phase and dual-phase technologies, respectively, each detector module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure