The molecular biology of apoptosis.

All multicellular organisms have mechanisms for killing their own cells, and use physiological cell death for defence, development, homeostasis, and aging. Apoptosis is a morphologically recognizable form of cell death that is implemented by a mechanism that has been conserved throughout evolution from nematode to man. Thus homologs of the genes that implement cell death in nematodes also do so in mammals, but in mammals the process is considerably more complex, involving multiple isoforms of the components of the cell death machinery. In some circumstances this allows independent regulation of pathways that converge upon a common end point. A molecular understanding of this mechanism may allow design of therapies that either enhance or block cell death at will.     

The biology of myocardial hibernation.

Patients with chronic coronary artery disease frequently have contractile dysfunction that recovers upon reperfusion. The concept of myocardial hibernation views the observed reduction in contractile function not as the result of an ongoing energetic deficit, but as an adaptive down-regulation that serves to maintain myocardial integrity and viability. In the experiment, sustained perfusion-contraction matching, recovery of energy and substrate metabolism during ongoing ischemia, the potential for recruitment of inotropic reserve, lack of necrosis, and therefore recovery of function upon reperfusion are established features of hibernation. Apart from reduced calcium responsiveness, the underlying mechanisms are still unclear. In patients, the importance of reduced baseline blood flow vs. that of superimposed repetitive stunning is somewhat controversial; however, in most studies blood flow is reduced, and the myocardium must be ischemic often enough to have persistent dysfunction. Morphologically, hibernating myocardium displays features of dedifferentiation, with loss of cardiomyocytes and myofibrils, and of degeneration, with increased interstitial fibrosis. Patients with hibernating myocardium must be identified and undergo revascularization. With a better understanding of the underlying mechanisms of hibernation, these adaptive responses to ischemia can potentially be recruited and reinforced pharmacologically to delay impending myocardial infarction.     

The biology of the mast cell.

Mast cells are ancient, versatile immune effector cells. On the one hand, they are endowed with unique effector capabilities and activation responses that initiate innate immunity to bacteria and are essential to host defense against helminthic parasites. On the other hand, they are the major effector of type I hypersensitivity and an important participant in a number of disease processes. This review focuses on the mechanisms of mast cell development, the cytokine control of this process, and the amplification of mast cell effector systems as an important determinant of disease.     

The isoprostanes in biology and medicine.

Isoprostanes are a new class of lipids, isomers of the conventional enzymatically derived prostaglandins, which are produced in vivo primarily by a free radical-catalyzed peroxidation of polyunsaturated fatty acids. F2-isoprostanes, isomers of the enzyme-derived prostaglandin F2alpha, are the most studied species, but analogous isomers of other prostaglandins and leukotrienes have been described. Because of their mechanism of formation, specific structural features that distinguish them from other free radical-generated products and chemical stability, they can provide a reliable index for the oxidant component of several diseases in vivo. Consistent data suggest that formation of F2-isoprostanes is altered in a variety of clinical settings putatively associated with oxidant stress. Moreover, measurement of F2-isoprostanes might provide a sensitive biochemical basis for dose-selection in studies of natural and synthetic antioxidants. Finally, some F2-isoprostanes possess potent biological activities in vitro and in vivo, suggesting that they may also act as mediators of the cellular effects of oxidative stress.     

The biology and pathology of oxygen radicals.

Superoxide radicals (O2-) are commonplace products of the biological reduction of oxygen. Their intrinsic reactivity and ability to generate other more reactive entities constitute a threat to cellular integrity. Superoxide dismutases, enzymes that catalytically scavenge these radicals, have evolved to meet this threat. These metalloenzymes are essential for respiring organisms to survive. Several compounds, such as the antibiotic streptonigrin and the herbicide paraquat, augment the production rate of O2- inside cells. This accounts for the oxygen-enhancement of their lethality. Some bacteria respond to this artificially increased rate of O2- production by synthesizing additional superoxide dismutase. Ionizing radiation generates O2- in its passage through oxygenated aqueous media, and superoxide dismutase added to the suspending medium, decreases the oxygen-enhancement of the lethality of such irradiation of the bacterium Escherichia coli. Production of O2- by activated neutrophils is clinically significant, since it is an important component of the bactericidal actions of these cells and the inflammatory process. Superoxide dismutases exert an anti-inflammatory action that may be useful in managing inflammations.     

The molecular biology of von Willebrand disease.

von Willebrand disease (VWD) is a common autosomally inherited bleeding disorder associated with mucosal or trauma-related bleeding in affected individuals. VWD results from either a quantitative or qualitative deficiency of von Willebrand factor (VWF)--a glycoprotein with essential roles in primary haemostasis and as a carrier of coagulation factor VIII (FVIII) in the circulation. In recent years the identification of mutations in the VWF gene in patients with VWD has improved our understanding of the structure and function of the VWF protein, and has illustrated the importance of specific regions of VWF for its interaction with other components of the vasculature. The underlying genetic lesions and associated molecular pathology have been identified in many cases of type 2A, type 2B, type 2M, type 2N and type 3 VWD. However in the most common variant, type 1 VWD, the causative molecular defect is unknown in the large majority of cases. In the absence of an understanding of the molecular pathology underlying type 1 VWD, precise diagnosis and classification of this common disorder remains problematic.     

Prostaglandin biology.

PGs are important mediators of normal physiology, response to injury, and pathologic processes. Dissecting these biochemical and molecular pathways allows development of therapeutic agents that can be [figure: see text] applied to specific clinical situations, while preserving PGs that play a role in normal physiology.