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Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl-ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free oxygen and nitrogen radicals, the rapid transcriptional activation of inflammatory cytokines, and the activation of PARP1. Inhibition of PARP attenuates neutrophil infiltration and inflammatory cytokine expression in the reperfused myocardium and preserves myocardial NAD+ and ATP. In addition, PARP inhibition increases the activation of myocyte survival enzymes protein kinase B (Akt) and protein kinase C epsilon (PKCε), and decreases the activity of myocardial ventricular remodeling enzymes PKCα/β, PKCζ/λ, and PKCδ. As a consequence, cardiomyocyte and vascular endo...

Acrolein is a highly reactive unsaturated aldehyde that is formed during the burning of gasoline and diesel fuels, cigarettes, woods and plastics. In addition, acrolein is generated during the cooking or frying of food with fats or oils. Acrolein is also used in the synthesis of many organic chemicals and as a biocide in agricultural and industrial water supply systems. The total emissions of acrolein in the United States from all sources are estimated to be 62,660 tons/year. Acrolein is classified by the Environmental Protection Agency as a high-priority air and water toxicant. Acrolein can exert toxic effects following inhalation, ingestion, and dermal exposures that are dose dependent. Cardiovascular tissues are particularly sensitive to the toxic effects of acrolein based primarily on in vitro and in vivo studies. Acrolein can generate free oxygen radical stress in the heart, decrease endothelial nitric oxide synthase phosphorylation and nitric oxide formation, form cytoplasmic and nuclear protein adducts with myocyte and vascular endothelial cell proteins and cause vasospasm. In this manner, chronic exposure to acrolein can cause myocyte dysfunction, myocyte necrosis and apoptosis and ultimately lead to cardiomyopathy and cardiac failure. Epidemiological studies of acrolein exposure and toxicity should be developed and treatment strategies devised that prevent or significantly limit acrolein cardiovascular toxicity.

In recent years there has been an increase in the use of traditional Asian medicines. It is estimated that 30% of the US population is currently using some form of homeopathic or alternative therapy at a total cost of over $13 billion annually. Herbal medications are claimed and widely believed to be beneficial; however, there have been reports of acute and chronic intoxications resulting from their use. This study characterizes a random sampling of Asian medicines as to the content of arsenic, mercury, and lead. Traditional herbal remedies were purchased in the USA, Vietnam, and China. The Asian remedies evaluated contained levels of arsenic, lead, and mercury that ranged from toxic (49%) to those exceeding public health guidelines for prevention of illness (74%) when consumed according to the directions given in or on the package. Heavy metals contained in Asian remedies may cause illness of unknown origin and result in the consumption of health care resources that are attributable to other causes. The public health hazards of traditional herbal Asian remedies should be identified and disclosed.

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Diphenylhydantoin was teratogenic and caused prenatal death in Swiss-Webster mice. Most deaths resulted after single treatment on days 10, 11, 12, 14, and 15. Fetal body weight was significantly reduced in a dose-related manner after single treatment on days 9 t o 15. Single injections of diphenylhydantoin produced open eye, ectrodactyly, cleft lip, cleft palate, hydronephrosis, and internal hydrocephalus. Skeletal defects noted were incomplete ossification of sternebrae or cervical centra, unfused sternebrae, and fused vertebrae. Long bones were shortened in a day-and dosage-dependent fashion. Mortality, teratogenesis, and effect on fetal growth were day-and dosage-dependent as was the spectrum of anomalies produced.

Introduction:Previous findings have demonstrated that preparedness and planning within the public health system are inadequately developed to respond to an act of biological or chemical terrorism.Materials and Methods:This investigation used Internet-based surveys to assess the level of preparedness (PL) and willingness to respond (WTR) to a bioterrorism attack, and identify factors that predict PL and WTR among Florida community healthcare providers. Invitations were sent to 22,800 healthcare providers in Florida, which resulted in 2,279 respondents.Results:Respondents included physicians (n=604), nurses (n=1,152), and pharmacists (n=486). The results indicated that only 32% of Florida healthcare providers were competent and willing to respond to a bioterrorism attack, 82.7% of providers were willing to respond in their local community, and 53.6% within the State. Respondents were more competent in administrative skills than clinical knowledge (62.8% vs. 45%). Areas in which respondents had the highest competency were the initiation of treatment and recognition of their clinical and administrative roles. Areas in which respondents showed the lowest competency were the ability to identify cases and the ability to communicate risk to others. About 55% of the subjects had previous bioterrorism training and 31.5% had conducted emergency drills. Gender, race, previous training and drills, perceived threats of bioterrorism attack, perceived benefits of training and drills, and feeling prepared were all predictors of overall preparedness.Conclusions:The findings suggest that only one-third of Florida community healthcare providers were prepared for a bioterrorism attack, which is an insufficient response rate to effectively respond to a bioterrorism incident.