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Extraction with 2 M lithium chloride removes a group of proteins (LiCl SP) from 50S ribosomal subunits. Both the LiCl SP and the resulting cores, which contain the remaining proteins as well as 5S and 23S RNA, lack peptidyl transferase activity, as measured by the "fragment reaction." Activity can be restored to the LiCl cores by reconstitution with LiCl SP under conditions of high temperature and high ionic strength. The LiCl SP proteins were fractionated by carboxymethyl-cellulose and Sephadex G-100, and the individual fractions were tested by this reconstitution system. Of the 18 ribosomal proteins found in the LiCl SP, only L16 is essential for reconstitution of peptidyl transferase activity.The discovery that peptidyl transferase is an integral part of ribosomal structure was of particular importance in focusing attention on the ribosome as an active participant in the translation process (1, 2). Since that time, the view has gradually emerged that many aspects of protein synthesis, such as translocation (3, 4), although mediated by nonribosomal factors, are intrinsic properties of the ribosome itself.In order to understand the peptidyl transferase reaction in terms of simple chemical mechanisms, it is essential to identify the ribosomal components involved, as well as the extraribosomal ligands with which they interact. Monro and coworkers have shown that under the conditions of the "fragment reaction," peptide bond formation is not dependent on the presence of the 30S ribosomal subunit, mRNA, intact tRNA, supernatant protein factors, or GTP (5). Although little is known about the identity of the riboso'Mal components involved in this function, it has been found that removal of a subset of proteins from the 50S subunit gives rise to inactive, protein-depleted "core" particles, and that reconstitution of the split proteins (SP) with the core particles restores activity (6). The latter observation suggested that one or more proteins that can be easily removed from the 50S subunit are essential for the peptidyl transferase function and presented a system that could be used to identify these proteins. An important step toward a molecular description of peptidyl transferase is the identification of these essential split protein components.

Prostaglandins of the E series have been shown to have immunosuppressive properties. To study the effects of the prostaglandin E1 analogue misoprostol on renal function and graft rejection after transplantation, we conducted a randomized, double-blind, placebo-controlled trial in 77 renal-allograft recipients. The subjects received misoprostol (200 micrograms four times daily by mouth; n = 38) or placebo (n = 39) for the first 12 weeks after transplantation, in addition to standard immunosuppression with cyclosporine and prednisone. They were then observed for an additional four weeks after the drug or placebo was discontinued. Treatment with misoprostol was associated with a significant improvement in renal function as judged by the mean (+/- SEM) serum creatinine concentration (128 +/- 7 vs. 158 +/- 11 mumol per liter after 12 weeks; P = 0.03) and creatinine clearance (84 +/- 6 vs. 69 +/- 5 ml per minute per 1.73 m2 of body-surface area; P = 0.05). There was a significant reduction in the incidence of acute rejection in the group treated with misoprostol as compared with the placebo group (10 of 38 vs. 20 of 39; P = 0.02), and there was less need for rehospitalization after transplantation (4 +/- 1 days with misoprostol vs. 10 +/- 2 days for placebo; P = 0.03). Although blood levels of cyclosporine did not differ significantly between the groups, they tended to be higher in the misoprostol group, as did the incidence of acute nephrotoxicity due to cyclosporine (13 of 38 vs. 8 of 39). Infectious complications tended to be fewer in the misoprostol-treated group (14 of 38 vs. 21 of 39). We conclude that misoprostol improves renal function and safely reduces the incidence of acute rejection in renal-transplant recipients treated concurrently with cyclosporine and prednisone.

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and +Research and Development, GD Searle and Company, Skokie. Illinois. USA Prostaglandins are reported to play an important regulatory role in cell-mediated immunity. The immunosuppressive properties of a new synthetic oral prostaglandin E 1 analogue, misoprostol, were studied in vivo in a rat heterotopic cardiac allograft model, and in 1·itro in mixed lymphocyte reaction. The results show that parenteral misoprostol, alone or in combination with low dose cyclosporin immunosuppressive therapy, significantly prolonged cardiac allograft survival compared with appropriate controls. Oral misoprostol alone in this model did not allow for measurable cardiac allograft prolongation. In vitro misoprostol demonstrated significant dose-response inhibition of the mixed lymphocyte culture assay. It is concluded that new prostaglandin E 1 analogues with oral bioavailability may have important applications to clinical transplantation in man, and may be cyclosporin sparing.

Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease, incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients, 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin, and no untoward effects were observed. Thus, atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.

Healthy cells from virtually all tissues synthesize a variety of prostaglandins, autacoids which can significantly alter cellular functions. An absolute or relative deficiency of prostaglandins has now been demonstrated in many diseases or clinical conditions. These include 'natural' disorders such as peptic ulcer disease and diabetes mellitus. These also include 'acquired' or iatrogenic conditions such as cyclosporine nephrotoxicity and the gastropathy induced by nonsteroidal anti-inflammatory drugs. We believe that the diversity of the disorders associated with prostaglandin deficiency may be wider and of greater pathogenetic importance than is currently recognized. We propose: 1) that prostaglandin deficiency will be demonstrated in many abnormalities which are now described as of uncertain etiology; and 2) that adverse effects from many commonly prescribed drugs may also be related to an unrecognized and unfavorable alteration in prostaglandin synthesis, disposal, or activity.