Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures.

Background: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques.

Duration of extremity tourniquet application profoundly impacts soft-tissue antibiotic exposure in a rat model of ischemia-reperfusion injury.

Introduction: Extremity tourniquet (TNK) application is an effective means of achieving compressible hemorrhage control in the emergency prehospital and clinical trauma setting. Modern United States military medical doctrine recommends TNK use to prevent lethal hemorrhage from extremity injury, followed by systemic prophylactic antibiotics to prevent wound infection. Because tissue pharmacokinetics of prophylactic antimicrobials during and after TNK-induced limb ischemia are largely unknown, this study was conducted to empirically determine the relationship between TNK application time and soft tissue antibiotic exposure in order to guide medical personnel in the management of extremity trauma.

Rapid degradation and non-selectivity of Dakin's solution prevents effectiveness in contaminated musculoskeletal wound models.

Background: Dakin's solution (buffered sodium hypochlorite) has been used as a topical adjunct for the treatment of invasive fungal infections in trauma patients. Prudent use of Dakin's solution (DS) for complex musculoskeletal wound management implies balancing antimicrobial efficacy and human tissue toxicity, but little empirical evidence exists to inform clinical practice. To identify potentially efficacious DS concentrations and application methods, we conducted two animal studies to evaluate the ability of DS to reduce bacterial burden in small and large animal models of contaminated musculoskeletal wounds.

Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPARγ/RXR and RAR/RXR: down-regulation of CYP27A1-LXRα signaling.

Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages [CES1KD (THP-1 cells with CES1 expression knocked down) macrophages] reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P45027A1 () in nonloaded and acLDL-loaded cells.

Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase.

NADPH oxidase (Nox)-derived oxyradicals contribute to atherosclerosis by oxidizing low-density lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2-AG), might be an important link between oxidative stress and atherosclerosis. We hypothesized that 2-AG biosynthesis in macrophages is enhanced following ligation of oxidized LDL by scavenger receptors via a signal transduction pathway involving Nox-derived ROS that activates diacylglycerol lipase-β (DAGL-β), the 2-AG biosynthetic enzyme.

The association of serum trans-nonachlor levels with atherosclerosis.

Recent epidemiological studies suggest a strong association between exposure to environmental contaminants, including organochlorine (OC) insecticides or their metabolites, and development of pathologies, such as atherosclerosis, in which oxidative stress plays a significant etiological role. Biomarkers of systemic oxidative stress have the potential to link production of reactive oxygen species (ROS), which are formed as a result of exposure to xenobiotic toxicants, and underlying pathophysiological states. Measurement of F2-isoprostane concentrations in body fluids is the most accurate and sensitive method currently available for assessing in vivo steady-state oxidative stress levels.

Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development.

Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity.

Organochlorine insecticides induce NADPH oxidase-dependent reactive oxygen species in human monocytic cells via phospholipase A2/arachidonic acid.

Bioaccumulative organohalogen chemicals, such as organochlorine (OC) insecticides, have been increasingly associated with disease etiology; however, the mechanistic link between chemical exposure and diseases, such as atherosclerosis, cancer, and diabetes, is complex and poorly defined. Systemic oxidative stress stemming from OC exposure might play a vital role in the development of these pathologies. Monocytes are important surveillance cells of the innate immune system that respond to extracellular signals possessing danger-associated molecular patterns by synthesizing oxyradicals, such as superoxide, for the purpose of combating infectious pathogens.

Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux.

Cholesterol cycles between free cholesterol (unesterified) found predominantly in membranes and cholesteryl esters (CEs) stored in cytoplasmic lipid droplets. Only free cholesterol is effluxed from macrophages via ATP-binding cassette (ABC) transporters to extracellular acceptors. Carboxylesterase 1 (CES1), proposed to hydrolyze CEs, is inactivated by oxon metabolites of organophosphorus pesticides and by the lipid electrophile 4-hydroxynonenal (HNE).

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition.

The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development.

Identification of palmitoyl protein thioesterase 1 in human THP1 monocytes and macrophages and characterization of unique biochemical activities for this enzyme.

The profiles of serine hydrolases in human and mouse macrophages are similar yet different. For instance, human macrophages express high levels of carboxylesterase 1 (CES1), whereas mouse macrophages have minimal amounts of the orthologous murine CES1. On the other hand, macrophages from both species exhibit limited expression of the canonical 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, MAGL.