The early detection of cytomegalovirus (CMV) reactivation after liver transplantation may fonn the basis of a pre-ernptive strategy for prevention of active CMV disease. We prospectively analyzed the clinical utility of weekly CMV plasma viral load determinations by quantitative PCR and the antigenemia assay in predicting CMV disease in 97 liver transplant recipients. CMV disease occurred in 21/97 (21.7%) patients a mean of 60 days post-transplant. Using a threshold of >400 copieslml plasma, PCR had a sensitivity of 100°h, specificity 47.4%, positive predictive value (PPV) 34.4 % and negative predictive value (NPV) 100% for prediction of CMV disease.Respective values for a positive antigenemia (threshold > O positive cells per 150,000 examined) were 95.2%, 55.3%, 37.0% and 97.7 %. Different eut-off points for a positive test were analyzed using receiver-operating characteristic curves. The optimal cut-off for viral load was in the range of 2000-5000 copieslml (sensitivity 85.7%, specificity 86.8%, PPV 64.3%, NPV 95.7% for > 5000 copieslrnl). The optimal cut-off for antigenemia was in the range of 4-6 positive cells/slide. Mean peak viral load in symptomatic patients was 73,715 copies perfml compared to 3615 copieslml in patients with asymptomatic CMV reactivation (p<0.001). In a multivariate logistic regression analysis of risk factors for CMV disease (CMV serostatus, acute rejection, and induction immunosuppression), peak viral load and Peak antigenemia emerged as the only significant independent predictors of CMV disease (for PCR, OR=1.40 per 1000 copy/ml increase in viral load, p=0.0001; for antigenemia OR=1.17 per 1 positive cell/slide). Plasma viral load by quantitative PCR is a useful test for predicting CMV disease, is at least as sensitive and specific as antigenemia, and could be employed as a marker in a pre-emptive strategy. Type of CMV disease in study patients Study schedule for patients enrolled in trial. ACKNOWLEDGEMENTS LIST OF FIGURES

Treatment of N-acylproline derivatives, 2, with acetic anhydride--dimethyl acetylenedicarboxylate (DMAD) gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (5). The reaction proceeds via a 1,3-dipolar addition of DMAD with the mesoionic oxazalone intermediate 3, generated in situ, with concomitant elimination of carbon dioxide. Reduction of 5 gave the diols 6 which upon subsequent acylation gave 1. The bis(N-methylcarbamate) 1d and the diacetate li show a modest level of in vivo antileukemia activity in the L1210 assay. A majority of the diesters, 1, showed significant antileukemic activity in the in vivo P-388 assay. The bis(carbamate) 1d afforded "cures" at dose levels as low as 12.5 mg/kg; 1 q showed potent activity at doses as low as 0.78 mg/kg. Several other compounds showed potent activity against P-388 over a greater than fourfold dose range with no acute toxicity. Half-lives for several diacetate derivatives of 1 were determined for aqueous Me2SO solutions. The preparation of 7 and 8 shows that 1 may react by O-alkyl ester cleavage.

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Hydrolysis of the title compound at pH 8 causes a color shift of 196 nm (438 → 634 nm). The total synthesis, kinetic parameters, and application in enzyme immunoassays are described.