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Protection Against Ischemia-Reperfusion Injury in the Liver
Ischemia-reperfusion (I/R) injury is an important cause of morbidity and mortality in hepatic resections and transplantations. It is well known that inflammation with neutrophil recruitment is a major component of I/R injury. Pharmacological agents that inhibit the effect of inflammatory mediators can attenuate I/R injury but do not block it. Another protective strategy against I/R injury is ischemic preconditioning. First described in myocardial injury, ischemic preconditioning consists of the repeated application of short periods of ischemia followed by reperfusion. Preconditioning may act by suppressing cytokines which can have both proinflammatory and apoptotic effects. Peralta et al (Am J Pathol 2002, 160:2111–2122) show that ischemic preconditioning in combination with overexpression of the anti-apoptotic gene Bcl-2 can prevent liver and lung damage after hepatic I/R in mice. The authors used several preconditioning protocols in Bcl-2 transgenic mice. Ischemic preconditioning in these animals completely prevented hepatic injury. These protective mechanisms likely involve decreased TNF release and reduction of MIP-2, thus inhibiting both inflammation and apoptosis.
Progression of Atherosclerosis by Recruitment of Circulating Monocytes
Macrophages are important components of atherosclerotic lesions of the arterial intima but there is a long-standing debate as to the origins of the cells in the lesions. They could derive from circulating monocytes or originate from cells present in the normal arterial wall. Understanding the origins of macrophages in atherosclerotic lesions may help to devise strategies that can prevent the progression of the lesions. Lessner et al (Am J Pathol 2002, 160:21452145–2155) used bone marrow transplantation to introduce cells with an allelic variant of the mouse common leukocyte antigen (CD45) in apoE knockout mice. This strategy made it possible to distinguish between host and donor-derived white blood cells in carotid artery lesions. Macrophage-derived foam cells in the intima lesions originated predominantly from circulating monocytes. In contrast, host cells predominated in the adventitial layer. The time course and spatial distribution of the adhesion molecules ICAM-1 and VCAM-1 was consistent with an important contribution of circulating monocytes to the initiation of the lesions in the arterial intima. Thus, novel techniques used in this work have provided significant new information to settle an old controversy.
Use of a "CardioChip" to Study Gene Expression in Cardiomyopathies
Barrans et al (Am J Pathol 2002, 160:2035–2043) describe the global analysis of gene expression in the left ventricular wall of patients with end-stage dilated cardiomyopathy undergoing heart transplantation. The analyses were performed using a cDNA microarray chip containing 10,848 heart-specific sequences. More than 100 transcripts were overexpressed in the myocardium of these patients relative to tissue from non-failing hearts. The "CardioChip" provides the opportunity to study in detail the molecular pathways involved in heart failure.
Collagen X Expression as a Linkage between Ossification and Hematopoiesis
Endochrondral ossification is the process by which non-calcified, avascular cartilage is replaced by bone trabeculae and marrow. The process is initiated by hypertrophy of cartilage with expression of collagen X. The expression is restricted to hypertrophic cartilage and is associated with mineralization, matrix remodeling, and vascular invasion. The newly established marrow provides the appropriate environment for hemoporetic cell proliferation, differentiation, and egress. Jacenko et al (Am J Pathol 2002, 160:2019–2034) examined whether transgenic mice overexpressing collagen X would develop skeletal as well as abnormalities in hematopoiesis. In 14 transgenic mouse lines with hypertrophic cartilage-specific expression of collagen X, the authors found phenotypes ranging from perinatal mortality to variable dwarfism. Mice with severe skeletal defects had associated marrow hypoplasia, lymphopenia, and increased risk for lymphosarcoma and other hemopoietic abnormalities. These results establish a linkage between endochondral ossification and hematopoiesis through the expression of collagen X in hypertrophic cartilage.
Arrested Differentiation in Wilms’ Tumor Correlates with the Expression of a Distinct Set of Genes
Wilms’ tumor (WT) is a well-known example of a tumor associated with arrested differentiation. At least two genes required for kidney development, PAX 2 and WT1, are expressed in these tumors. Nevertheless, no systematic analysis of gene expression in WTs has been undertaken so far. Li et al (Am J Pathol 2002, 160:2181–2190) did a survey of patterns of gene expression in WTs using oligonucleotide arrays. Expression of genes corresponding to the earliest stage of metanephric development was high in WTs while genes corresponding to later stages were down-regulated. The authors identified a set of 27 genes which were highly expressed in WT tumors relative to normal fetal kidney and heterologous tumors. Included in this set are genes necessary for cell survival and proliferation in early metanephric development as well as genes coding for transcription factors, receptors, and tumor antigens. The data pinpoint the stage in kidney development at which arrested differentiation occurs in WTs and identify a cluster of genes that may be of importance for diagnosis and treatment follow-up.
Tau Pathology in Corticobasal Degeneration Defines a Distinct Entity
Tau is a phosphoprotein that regulates microtubule assembly and stability. Neurological diseases, including Alzheimer’s disease and corticobasal degeneration (CBD) associated with tau abnormalities are collectively referred to as tauopathies. CBD is a progressive neurological disease characterized by posture and motor function abnormalities, most frequently without dementia. Tau aggregates in neurons and glia of CBD patients are predominantly composed of hyperphosphorylated tau with four microtubule binding repeats (4R-tau). Astrocytes and oligodendiocytes in gray and white matter contain tau inclusions detectable by immunohistochemistry and Western blot analysis. Forman et al (Am J Pathol 2002, 160:2045–2053) studied in detail the tau pathology of 12 CBD patients. Despite the extensive heterogenerity of tau abnormalities found among these patients, there was a common phenotype among them, characterized by widespread aggregation of 4R-tau throughout the brain. The data suggest that although CBD is clinically heterogeneous, it can be considered as a distinct lobar and basal ganglia tauopathy.
Virus Visualization by Atomic Force Microscopy
The structure of complex human and animal viruses is difficult to visualize. Because of their large sizes it is often not possible to make use of x-ray crystallography for these analyses but x-ray diffraction and cryo-electron microscopy have provided important information. Plomp et al (Am J Pathol 2002, 160:1959–1966) describe a method to visualize herpes simplex virus-1 by atomic force microscopy (AFM). The method permits the visualization of individual virus particles in solution in relative crude preparations. Samples are usually simply dried in air, without freezing, fixation, or staining. The authors present images of intact enveloped viruses of various components of the viral structure and of extruded viral DNA. During the last 10 years, AFM has evolved into a relatively easy-to-use tool to study viruses in simple preparations at a high resolution.
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