The neutrophil is an essential component of the innate immune system, and its function is vital to human life. Its production increases in response to virtually all forms of inflammation, and subsequently, it can accumulate in blood and tissue to varying degrees. Although its participation in the inflammatory response is often salutary by nature of its normal interaction with vascular endothelium and its capability to enter tissues and respond to chemotactic gradients and to phagocytize and kill microrganisms, it can contribute to processes that impair vascular integrity and blood flow. The mechanisms that the neutrophil uses to kill microorganisms also have the potential to injure normal tissue under special circumstances. Its paradoxical role in the pathophysiology of disease is particularly, but not exclusively, notable in seven circumstances: 1) diabetic retinopathy, 2) sickle cell disease, 3) TRALI, 4) ARDS, 5) renal microvasculopathy, 6) stroke, and 7) acute coronary artery syndrome. The activated neutrophil's capability to become adhesive to endothelium, to generate highly ROS, and to secrete proteases gives it the potential to induce local vascular and tissue injury. In this review, we summarize the evidence for its role as a mediator of tissue injury in these seven conditions, making it or its products potential therapeutic targets.

Studies on obesity and the risk for hematological malignancies are reviewed. The paper includes a discussion of the metabolic effects of obesity and their possible role in linking increased body fat to neoplasia.

A B S T R A C T Suspensions of leukemic lymphocytes and myeloblasts and blood of leukemic patients were studied to examine (a) the effect of leukemic cells on blood viscosity and (b) the ability of leukemic cells to traverse channels of capillary diameter. The viscosity of suspensions of leukemic cells was dependent logarithmically on (a) shear strain rate and (b) cytocrit, although, suspensions of small lymphocytes and of myeloblasts had a similar viscosity at equivalent shear rates and cytocrit. The minimum apparent viscosity (MAV) of leukemic cells and red blood cells, measured over shear rates of 2.3-230 s-' was dependent logarithmically on cytocrit.However, MAV was slightly greater for leukemic cells than for red cells at cytocrits up to 20%. At cytocrits above 20%, MAV of leukemic cells increased more rapidly than that of erythrocytes. For example, at a 15% cytocrit MAVWBC (1.85 centipoise) was only slightly greater than MAVRBC (1.59); whereas, at 45% cytocrit MAVWBC (14.9) was markedly greater than MAVRsc (3.81).The blood of subjects with leukemia with marked elevation of leukocyte concentration (leukocrits of 6-32%) had 24% higher mean MAV (3.72) than blood with a similar total cytocrit composed of red cells (3.00).A negative correlation was present between leukocrit and erythrocrit in chronic lymphocytic (r = -0.82) and chronic granulocytic (r =-0.81) leukemia. Therefore, the modest increase in whole blood MAV in leukemia can be explained by (a) the negative association of leukocrit and erythrocrit and (b) the rarity of leukocrits over 20% and total cytocrits over 45%. However, the MAV

The effect of the chemotatic peptide, N-formylmethionylleucylphenylalanine (FMLP), on actin conformation in human neutrophils (PMN) was studied by flow cytometry using fluorescent 7-nitrobenz-2-oxa-l,3-diazole (NBD)-phallacidin to quantitate cellular Factin content. Uptake of NBD-phallacidin by fixed PMN was saturable and inhibited by fluid phase F-actin but not G-actin. Stimulation of PMN by >1 nM FMLP resulted in a dosedependent and reversible increase in F-actin in 70-95% of PMN by 30 s. The induced increase in F-actin was blocked by 30 #M cytochalasin B or by a t-BOC peptide that competitively inhibits FMLP binding. Under fluorescence microscopy, NBD-phallacidin stained, unstimulated PMN had faint homogeneous cytoplasmic fluorescence while cells exposed to FMLP for 30 s prior to NBD-phallacidin staining had accentuated subcortical fluorescence. In the continued presence of an initial stimulatory dose of FMLP, PMN could respond with increased F-actin content to the addition of an increased concentration of FMLP. Thus, FMLP binding to PMN induces a rapid transient conversion of unpolymerized actin to subcortical F-actin and repetitive stimulation of F-actin formation can be induced by increasing chemoattractant concentration. The directed movement of PMN in response to chemoattractant gradients may require similar rapid reversible changes in actin conformation.

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