Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20+ cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20+ cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20+ cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

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The complement mediated binding of prepared antib~dy/~H-dsDNA immune complexes to the red blood cells obtained from a number of patient populations has been investigated. Patients with solid tumors have binding activity similar to that seen in a normal group of individuals. However, a significant fraction of patients with systemic lupus erythematosus, rheumatoid arthritis, and hematologic malignancies have lowered binding activity compared with normal subjects. Quantitative studies indicate the lowered activity probably arises due to a decrease in complement receptors on the respective red blood cells. The potential importance and implications of these findings are briefly discussed. It is well established that complement-fixing antibody/dsDNA immune complexes play a key role in the pathogenesis of SLE (17,18). We have previously performed quantitative experiments (5-8) which demonstrate that large, soluble antibody/dsDNA immune complexes bind to the CR, receptors of normal human

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The evolution of concepts and definitions of agricultural systems over time is presented. Inputs of an agricultural system are classified as components and activities. A component is either a resource or a technology. The activities are the management of resources and the application of technology in the production process. The outputs of a production process will include both the targeted product and the environmental impact. When these terms are used to describe an agricultural system graphically, the dynamic aspects of the system can easily be illustrated and problems associated with the system can be properly identified. Sustainable agriculture is recognized as conveying certain objectives or delineating certain requirements of an agricultural system, in terms of both the input and output of the system. These objectives are: (1) producing necessary quantity of high quality food and fiber; (2) profitable to the grower; (3) conserving nonrenewable resources; and (4) harmonious with biological, physical and social environments. These objectives have long‐term implications and attempt to secure the future viability of agriculture. Therefore they embrace the concept of sustainability. The difficulty of constructing such a system is that not all the objectives are compatible; compromise or trade‐offs among the objectives are often necessary in developing a workable sustainable system. Progress and improvement can always be made through research, but no perfect system can realistically be constructed. General research issues in sustainable agriculture are discussed. Priorities in developing appropriate technology based on sound biological principles and laws of physics and mechanics for pest and weed control are suggested.

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Platelets and von Willebrand factor play pathogenetic roles in atherosclerosis and acute coronary artery ischemic syndromes. Patients with Bernard-Soulier Syndrome are deficient in several platelet membrane glycoproteins, including glycoprotein Ib (GpIb). Glycoprotein Ib is the primary platelet receptor for von Willebrand factor and plays a critical role in the initiation of thrombus formation. Glycoprotein Ib, but also GpIIb/IIIa, mediates the adhesion of platelets to damaged endothelium, particularly at the high shear stresses found in small or diseased arteries. A patient with Bernard-Soulier syndrome is described who developed coronary artery atherosclerosis and unstable angina requiring coronary artery bypass grafting. The implications of this experiment in nature on the contribution of platelets and platelet GpIb and GpIIb/IIIa receptors to the development of atherosclerosis and unstable angina are discussed.