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Importance Most individuals who die of sudden cardiac death (SCD) display very advanced lesions of atherosclerosis in their coronary arteries. Thus, we sought to identify and characterize a putative subpopulation of young individuals exhibiting accelerated coronary artery atherosclerosis. Objective Our analysis of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study—which examined 2651 individuals, obtaining quantitative measurements of traditional risk factors for coronary heart disease (CHD)—aimed to identify individuals with advanced coronary artery lesions, and to determine whether risk factors could account for such rapid disease progression, or not. Design Using the cross-sectional PDAY study data, an exploratory de facto analysis stratified the population by age and observed number of coronary raised lesions and examined these groups via Poisson regression modeling. A separate de novo approach utilized Poisson mixture modeling to generate low- and high-growth groups based on measurements of traditional risk factors, and identified factors contributing to disease progression. Participants Participants, n = 2651 individuals aged 15–34, who had died of non-cardiac death, were recruited post mortem. Tissues and other samples were harvested for analysis (details in previously published PDAY studies). Main Outcome(s) and Measure(s). Using quantitative measurements of raised coronary lesions and traditional risk factors of CHD, we sought to identify which risk factors account for disease progression. Results A group of ~13% of the PDAY population exhibits accelerated coronary atherosclerosis despite their young age. Several traditional risk factors were associated with increased odds of inclusion in this subgroup, reflecting current understanding of these markers of disease. However, only age was a significant contributing factor to the observed coronary lesion burden. Conclusions While a range of traditional risk factors contribute to an individual's inclusion to the identified subgroup with accelerated atherosclerosis, these factors, with the exceptions of age, are not able to predict an individual's lesion burden. Moreover, unattributed variances in observations indicate the need to study novel risk factors. Short summary Hypothesis The extent of coronary atherosclerotic disease is limited and homogeneous within youth, and its progression can be accounted for by traditional risk factors in this population. Findings A subpopulation (~13%) of the Pathobiological Determinants of Atherosclerosis in Youth cohort exhibited accelerated coronary artery atherosclerosis. While several traditional risk factors contribute to an individual's inclusion in this subgroup, these factors, with the exceptions of age, do not predict accurately an individual's lesions burden. Critically, unattributed variances in observations indicate the need for the identification of novel risk factors. Meaning Screening of the general population at a young age for high-risk group membership could provide opportunity for disease prevention and avoidance of the worse complications such as myocardial infarction and sudden cardiac death later in life.

Compare the in vitro efficacy of hypochlorous acid 0.01% (HA), povidone iodine 5% (PI), chlorhexidine gluconate 4% (CHG), and isopropyl alcohol 70% (IPA) against common skin microorganisms.Time-kill studies were conducted against methicillin-susceptible Staphylococcus aureus (MSSA) and Staphylococcus epidermidis (MSSE), methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE), Candida albicans, Corynebacterium species (striatum and amycolatum), Propionibacterium acnes, Pseudomonas aeruginosa, Streptococcus pyogenes, Staphylococcus capitis, and Staphylococcus xylosus.Methicillin-resistant S. aureus: Bactericidal effect was immediate for HA and IPA. For PI and CHG, the effect occurred at 1 and 10 minutes, respectively. Methicillin-resistant S. epidermidis: Hypochlorous acid, IPA, and PI had immediate bactericidal effects, whereas CHG required 1 minute. Methicillin-susceptible Staphylococcus aureus: All agents had bactericidal effects at 1 minute. C. species, S. pyogenes, P. aeruginosa, and P. acnes: All antiseptics demonstrated immediate bactericidal effects. Methicillin-susceptible Staphylococcus epidermidis and S. capitis: Hypochlorous acid and IPA had immediate effect, whereas PI and CHG required 1 minute. C. albicans: Hypochlorous acid, IPA, and PI were immediately bactericidal, whereas CHG required 1 minute. S. xylosus: Hypochlorous acid and CHG were immediately bactericidal, whereas IPA and PI required 1 and 2 minutes, respectively.In vitro studies of HA 0.01% were observed to have equal or more efficacious antiseptic properties compared with IPA, CHG, and PI. Future studies will be needed to investigate its role in periocular use.

The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological β-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase.

A considerable volume of research over the last decade has focused on understanding the fundamental mechanisms for the progression of atherosclerosis-the underlying cause for the vast majority of all cardiovascular (CVD)-related complications. Aging is the dominant risk factor for clinically significant atherosclerotic lesion formation, yet the heightened impact of aging on the disease is not accounted for by changes in traditional risk factors, such as lack of physical activity, smoking, hypertension, hyperlipidemia, or diabetes mellitus. This review will examine the pathological and biochemical processes of atherosclerotic plaque formation and growth, with particular focus on the aging risk vis-a-vis arterial homeostasis. Particular focus will be placed on the impact of a number of important contributors to arterial homeostasis including bone marrow (BM)-derived vascular progenitor cells, differential monocyte subpopulations, and the role of cellular senescence. Finally, this review will explore many critical observations in the way the disease process has been reassessed both by clinicians and researchers, and will highlight recent advances in this field that have provided a greater understanding of this aging-driven disease.

The process of controlled cellular death known as apoptosis has an important central role not only in normal homeostatic maintenance of tissues, but also in numerous diseases such as cancer, neurodegenerative, autoimmune, and cardiovascular diseases. As a result, new technologies with the capability to selectively detect apoptotic cells represent a central focus of research for the study of these conditions. We have developed a new biosensor for the detection of apoptotic cells, incorporating the targeted selectivity for apoptotic cells from Annexin V with the sensitivity of bioluminescence signal generation from a serum-stable mutant of Renilla luciferase (RLuc8). Our data presents a complete characterization of the structural and biochemical properties of this new Annexin-Renilla fusion protein (ArFP) construct, as well as a validation of its ability to detect apoptosis in vitro. Moreover, this work represents the first report of a bioluminescent Annexin V apoptosis sensor utilized in vivo. With this new construct, we examine apoptosis within disease-relevant animal models of surgery-induced ischemia/reperfusion, corneal injury, and retinal cell death as a model of age-related macular degeneration. In each of these experiments, we demonstrate successful application of the ArFP construct for detection and bioluminescence imaging of apoptosis within each disease or treatment model. ArFP represents an important new tool in the continuously growing kit of technologies for apoptosis detection, and our results from both in vitro and in vivo experiments suggest a diverse range of potential clinically relevant applications including cancer therapeutic screening and efficacy analysis, atherosclerosis and cardiovascular disease detection, and the monitoring of any number of other conditions in which apoptosis has a central role.

Sudden Cardiac Death (SCD) is responsible for at least 180,000 deaths a year and incurs an average cost of $286 billion annually in the United States alone. Herein, we present a novel discrete event simulation model of SCD, which quantifies the chains of events associated with the formation, growth, and rupture of atheroma plaques, and the subsequent formation of clots, thrombosis and on-set of arrhythmias within a population. The predictions generated by the model are in good agreement both with results obtained from pathological examinations on the frequencies of three major types of atheroma, and with epidemiological data on the prevalence and risk of SCD. These model predictions allow for identification of interventions and importantly for the optimal time of intervention leading to high potential impact on SCD risk reduction (up to 8-fold reduction in the number of SCDs in the population) as well as the increase in life expectancy.