University of Kentucky

About: University of Kentucky is a education organization based out in Lexington, Kentucky, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 43933 authors who have published 92195 publications receiving 3256087 citations. The organization is also known as: UK.

Advances in the Understanding of Myocarditis

Abstract: Myocarditis is a poorly understood disease because it progresses through stages with distinctly different mechanisms and manifestations. The objective of this article is to better define myocarditis for both clinicians and clinical scientists by setting it in the framework of 3 phases of disease. In phase 1, the viral stage, we review recent discoveries about the way viruses gain access to target tissue and how they trigger immune responses. In the second, autoimmune phase of disease, we examine the roles of autoreactive T cells, cytokines, and cross-reacting antibodies and reconsider the relevance of recent therapy trials. In the third phase of the disease, dilated cardiomyopathy, we consider the remodeling processes. We then offer current recommendations for diagnosis and therapy and conclude with a look to the future. Myocarditis is a continuum of 3 distinct disease processes, one evolving into the other with transitional periods of indistinctness. For each of the 3 processes, pathogenesis, diagnosis, and treatment differ considerably. Without precise knowledge of the point to which an individual patient’s myocarditis has evolved in this continuum, the clinician can only use diagnostic tools and therapeutic interventions haphazardly. It is likely that the majority of cases of myocarditis, except in countries in which Chagas’ disease or diphtheria is common, result from viral infection, which may progress to an autoimmune phase after resolution or reduction of the initial infection, and then finally to progressive dilatation after resolution or reduction of the autoimmune injury (Figure 1). A viral cause can only be proved by direct molecular or indirect methods. Appropriate treatment at the viral stage is eradication of virus and amelioration of viral injury. The autoimmune phase can be diagnosed by endomyocardial biopsy, supplemented by serological markers of immune activation. Immune suppression is probably the most appropriate therapy in this stage, unless significant viral …

Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo

Abstract: Cyclic ADP-ribose is believed to be an important calcium-mobilizing second messenger in invertebrate, mammalian and plant cells. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cyclic ADP-ribose in vivo. Using CD38-deficient mice, we demonstrate that the loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38-deficient neutrophils to directionally migrate to the site of infection. Furthermore, we show that cyclic ADP-ribose can directly induce intracellular Ca++ release in neutrophils and is required for sustained extracellular Ca++ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP). Finally, we demonstrate that neutrophil chemotaxis to fMLP is dependent on Ca++ mobilization mediated by cyclic ADP-ribose. Thus, CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses.

Coronary Composition and Macrophage Infiltration in Atherectomy Specimens From Patients With Diabetes Mellitus

Abstract: Background—Lipid-rich, inflamed atherosclerotic lesions are associated with plaque rupture and thrombosis, which are the most important causes of death in patients with diabetes mellitus This study was designed to quantify lipid composition and macrophage infiltration in the coronary lesions of patients with diabetes mellitus Methods and Results—A total of 47 coronary atherectomy specimens from patients with diabetes mellitus were examined and compared with 48 atherectomy specimens from patients without diabetes Plaque composition was characterized by trichrome staining Macrophage infiltration was characterized by immunostaining Clinical and demographic data were similar in both groups The percentage of total area occupied by lipid-rich atheroma was larger in specimens from patients with diabetes (762%) than in specimens from patients without diabetes (261%; P5001), and the percentage of total area occupied by macrophages was larger in specimens from patients with diabetes (2263%) than in specimens from patients without diabetes (1261%; P50003) The incidence of thrombus was also higher in specimens from patients with diabetes than in specimens from patients without diabetes (62% versus 40%; P5004) Plaque composition, macrophage infiltration, and thrombus were similar in lesions from diabetic patients treated with insulin compared with lesions from patients treated with sulfonylureas or diet Conclusions—Coronary tissue from patients with diabetes exhibits a larger content of lipid-rich atheroma, macrophage infiltration, and subsequent thrombosis than tissue from patients without diabetes These differences suggest an increased vulnerability for coronary thrombosis in patients with diabetes mellitus (Circulation 2000;102:2180-2184)

Caspase and calpain substrates: Roles in synaptic plasticity and cell death

Abstract: Neurons are an unusual type of cell in that they send processes (axons and dendrites) over great distances. This elaborate morphology, together with their excitability, places neurons at risk for multiple insults. Recent studies have demonstrated that apoptotic and excitotoxic mechanisms not only contribute to neuronal death, but also to synaptic dysfunction and a breakdown in neural circuitry (see Mattson and Duan [1999] J. Neurosci. Res. 58:152-166, this issue). Proteases of the caspase and calpain families have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. Caspases and calpains are cysteine proteases that require proteolytic cleavage for activation. The substrates cleaved by caspases include cytoskeletal and associated proteins, kinases, members of the Bcl-2 family of apoptosis-related proteins, presenilins and amyloid precursor protein, and DNA-modulating enzymes. Calpain substrates include cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters, and steroid receptors. Many of the substrates of caspases and calpains are localized in pre- and/or postsynaptic compartments of neurons. Emerging data suggest that, in addition to their roles in neurodegenerative processes, caspases and calpains play important roles in modulating synaptic plasticity. The present article provides a review of the properties of the different caspases and calpains, their roles in cell death pathways, and the substrates upon which they act. Emerging data are considered that suggest key roles for these proteases in the regulation of synaptic plasticity.

A Correlation-Based Transition Model Using Local Variables—Part II: Test Cases and Industrial Applications

Abstract: A new correlation-based transition model has been developed, which is built strictly on local variables. As a result, the transition model is compatible with modern computational fluid dynamics (CFD) methods using unstructured grids and massive parallel execution. The model is based on two transport equations, one for the intermittency and one for the transition onset criteria in terms of momentum thickness Reynolds number. The proposed transport equations do not attempt to model the physics of the transition process (unlike, e.g., turbulence models), but form a framework for the implementation of correlation-based models into general-purpose CFD methods. Part I of this paper (Menter, F. R., Langtry, R. B., Likki, S. R., Suzen, Y. B., Huang, P. G., and Volker, S., 2006, ASME J. Turbomach., 128(3), pp. 413–422) gives a detailed description of the mathematical formulation of the model and some of the basic test cases used for model validation. Part II (this part) details a significant number of test cases that have been used to validate the transition model for turbomachinery and aerodynamic applications, including the drag crisis of a cylinder, separation-induced transition on a circular leading edge, and natural transition on a wind turbine airfoil. Turbomachinery test cases include a highly loaded compressor cascade, a low-pressure turbine blade, a transonic turbine guide vane, a 3D annular compressor cascade, and unsteady transition due to wake impingement. In addition, predictions are shown for an actual industrial application, namely, a GE low-pressure turbine vane. In all cases, good agreement with the experiments could be achieved and the authors believe that the current model is a significant step forward in engineering transition modeling.