Toradol is a new parenteral, nonsteroidal anti-inflammatory drug which is efficacious in treating renal coli. In the present experiments, Toradol was administered to both control dogs and dogs with unilateral ureteral obstruction. In control dogs, Toradol had no effect on RBF or GFR, despite inhibition of renal prostaglandin synthesis (measured as urinary prostaglandin release). In contrast, RBF fell acutely by 35% (p < 0.001) within 15 minutes of Toradol administration in the setting of ureteral obstruction; contralateral RBF was unaffected. Ipsilateral ureteral pressure also fell. Changes in RBF and ureteral pressure, together with the known effects of NSAIDs on pain pathways, may contribute to the pain relief observed clinically with Toradol. However, the abrupt changes in renal hemodynamics brought on by Toradol to the obstructed kidney may compromise renal reserve, and Toradol should be used cautiously in treating renal colic.
A few percent of mouse splenocytes express isotypes characteristic of the secondary response together with IgM, and some cells express these isotypes alone. We isolated populations of small memory cells that express (t) IgM but not IgG1, (it) IgM but not IgA, (iii) IgM and IgG1, (iv) IgM and IgA, and (v) IgG1 but not IgM. We have analyzed their DNA to show that there has been no switch recombination or deletion in the Ig constant region (C) genes. Using sandwich RNA hybridizations, we have found that cells expressing IgG1 contain nuclear RNAs that have both C., and Cy1 sequences, and that cells expressing IgA contain nuclear RNAs that have both C,. and C, sequences. We propose that the expression of an isotype characteristic of the secondary response in memory cells is accomplished by alternative RNA processing of large (up to 180 kilobases) nuclear RNA transcripts that span the heavy chain gene locus.During the immune response, the antibody populations shift from IgM to IgG, IgA, and IgE. After the primary, IgM response, memory cells that express surface IgG, IgE, or IgA appear in the spleen (1). This surface Ig is indicative of the isotype and allotype of the antibody that the progeny of these memory cells will secrete upon antigenic restimulation.The initial ,u heavy chain is encoded by a gene with a heavy chain (H) variable-region exon, assembled by DNA recombination that joins heavy chain variable (VH), diversity (D), and joining (JH) segments (2, 3), that is attached by a long intron to the exons of the constant region C,,. The expression of membrane-bound and secreted forms of IgM is regulated by RNA splicing, which adds alternative exons to the COOH-terminal sequence (4, 5). How do Ig molecules of the same antigen specificity but with one of the other heavy chain constant regions arise? In plasma cells, a second type of DNA rearrangement, which deletes the DNA between S., the switch region between VH-D-JH and C., and the switch region 5' to the expressed heavy chain constant region gene, enables heavy chain class switching to occur (6, 7). The assembled VH gene is thus brought near the CH gene of the class to be expressed, and protein expression occurs by the splicing of VH-D-JH RNA to the proximal CH RNA exons. Each switch region begins 1-4 kilobases (kb) 5' to CH, and the short repetitive sequences extend another 1 kb (Se) to 10 kb (Syl) 5' (8). This gene deletion model explains the mechanism of Ig expression in the secreting plasma cell (9, 10). Does it hold for memory cells?We used fluorescence-activated cell sorting to purify memory cells of the secondary response. To ensure that all surface Igs were endogenously synthesized, washed spleen cells were trypsinized to remove surface proteins and incubated in cell culture to allow protein reexpression. Then we sorted the cells for a first isotype and repeated the trypsinization and cell culture before staining and sorting on the basis of a second isotype. To avoid direct binding of typing antibodies to cellular Fc receptors, we used purified F(...
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