FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the inflammatory response have shown only modest clinical benefit. Recently, interest has shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction. ⋯ Apoptosis proceeds via auto-activation of cytosolic and/or mitochondrial caspases, which can be influenced by the pro- and anti-apoptotic members of the Bcl-2 family. In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis represents an attractive therapeutic target for the septic patient.
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General anesthesia markedly impairs normal control of body temperature, reducing the threshold (triggering core temperature) for thermoregulatory vasoconstriction from approximately 37 to approximately 34.5 degrees C. Sweating and active vasodilation thresholds similarly are increased, widening the range of temperatures not triggering regulatory compensations from approximately 0.2 to approximately 4 degrees C. However, once initiated, the gains (slopes of response intensity vs. core temperature curves) and maximum intensities of thermoregulatory responses are nearly normal. ⋯ Core hypothermia provokes thermoregulatory responses including vasoconstriction (above the block level) and shivering. Nonetheless, many patients feel warmer after induction of regional anesthesia, apparently because perceived skin temperature is elevated. The following review will focus on anesthetic-induced impairment of normal thermoregulatory control and the resulting alterations in heat balance.
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A new strategy for the delivery of cytotoxic agents to solid tumors is described in which monoclonal antibodies are used as carriers for enzymes to tumor cell surfaces. The enzymes are chosen for their abilities to convert relatively noncytotoxic drug precursors (pro-drugs) into active anticancer drugs. The drugs thus formed can then penetrate into nearby tumor cells, resulting in cell death. ⋯ The enzymes have been shown to localize into tumors when linked to monoclonal antibodies that bind to tumor-associated antigens. In vivo studies indicate that MAb-enzyme/prodrug combinations can result in antitumor activities significantly greater than those of the prodrugs or drugs given alone. This is most likely due to the generation of large amounts of active drug at the tumor site.