Induction of endogenous cytokine-mRNA in circulating peripheral blood mononuclear cells by IL-2 administration to cancer patients

The lymphokine IL-2 plays a central role in immune regulation. Recent clinical trials have shown that when administered systemically either alone, or in combination with lymphokine-activated killer cells, IL-2 can cause regression of metastatic tumors in some patients with a variety of otherwise refractory cancers. To evaluate the mechanism of in vivo action of IL-2, as well as the toxicity associated with its administration, we have studied the in vivo cytokine-mRNA expression of circulating PBMC in cancer patients undergoing treatment with high dose IL-2. Before IL-2 administration, we found low level or no evidence of cytokine-mRNA expression in PBMC. After IL-2 infusion, circulating PBMC showed enhanced proliferative activity and contained significant levels of mRNA for TNF-alpha and IL-6 as well as mRNA for the p55 IL-2R, Tac, but no mRNA coding for granulocyte-monocyte-CSF and TNF-beta (lymphotoxin). IL-1 beta mRNA was expressed at very low levels in circulating PBMC after IL-2 infusion. Each of these cytokine -mRNA was, however, inducible in vitro by stimulation of PBMC with IL-2 alone. The results of these in vivo studies suggest that IL-2 may be a physiologic inducer of TNF and IL-6 which, because of their pleiotropic effects, may be important endogenous signals in the body's immune response and account for some of the physiologic changes seen in patients receiving high dose IL-2.     

Consent’s dominion: Dementia and prior consent to sexual relations

In this paper, I answer the following question: suppose that two individuals, C and D, have been in a long‐term committed relationship, and D now has dementia, while C is competent; if D agrees to have sex with C, is it permissible for C to have sex with D? Ultimately, I defend the view that, under certain conditions, D can give valid consent to sex with C, rendering sex between them permissible. Specifically, I argue that there is compelling reason to endorse the Prior Consent Thesis, which states the following: D, when competent, can give valid prior consent to sex with her competent partner (C) that will take place after she has dementia, assuming that D is the same person as she was when she gave prior consent, meaning that, if D, when competent, gave prior consent to sex with C, then C may permissibly have sex with D. In Section 2, I explain both the background and the existing literature on this issue. In Section 3, I outline relevant stipulations about the kinds of cases I will be examining. In Section 4, I defend the Prior Consent Thesis. And, in Section 5, I address objections to the Prior Consent Thesis.     

What holds us together? Why do some of us fall apart? What can we do about it?

One of the intriguing questions about complex organisms is, What holds them together? One of the principal answers is the rough, fibrous material known as collagen. A related question is, How is collagen made? The biosynthesis of the protein has several unusual features. One is the extensive use of the principle of spontaneous self-assembly seen in the formation of crystals. The three polypeptide chains of the protein fold into a triple-helical conformation by a process that begins with the formation of a small nucleus of triple helix at the C-terminus of the molecule and then propagation of the nucleus in a zipper-like fashion. Also, the self-assembly of the collagen monomers into fibrils is an entropy driven, crystallization-like process. Why do some of them fall apart? Mutations that alter the expression or primary structure of collagen are the predominant causes of severe skeletal defects such as osteogenesis imperfecta and chondrodysplasias. Mutations that have milder effects on the synthesis or structure of the protein are found in a subset of patients with more common diseases such as osteoporosis and early onset osteoarthritis. What can we do about the defects in collagen? Recent results have emphasized the importance of earlier observations that bone marrow contains a small subset of cells that are progenitors of osteoblasts, chondroblasts and several other types of non-hematopoietic cells. After systemic infusion into irradiated mice, the infused cells slowly replace a small fraction of the cells in bone, cartilage, lung and several other tissues. Therefore, the results suggest that the cells, known as mesenchymal stem cells or marrow stromal cells, can be used for both cell and gene therapy of diseases in which bone, cartilage and other connective tissues fall apart.