Background: Primary Epstein-Barr virus (EBV) infection frequently occurs early after transplantation (Tx) in seronegative pediatric heart Tx recipients who receive organs from seropositive donors and is the key risk factor for the development of post-transplant lymphoproliferative disorder (PTLD). The routine use of post-Tx EBV-PCR monitoring offers the opportunity to study the time course of primary EBV infection and the influence of differing immunosuppressive regimens. Methods: We studied 15 consecutive seronegative recipients who received a primary heart Tx from a seropositive donor. All were managed with tacrolimus-based immunosuppression with 9/15 also receiving 5 days of induction with rabbit antithymocyte globulin (Thymoglobulin). Surveillance was by whole blood real-time EBV-PCR approximately monthly for the first 6 months, then every 2 months for 6 months, then approximately quarterly thereafter. Results: Mean age at transplant was 5.4 years, and mean donor age was 8 years. Positive donor EBV serostatus prior to any donor transfusion was confirmed in 6 cases. One patient developed PTLD. A total of 270 PCR measurements were made (average 18/pt). 12/15 experienced primary EBV infection with first positive PCR 24-307 days post-Tx; median 38 days (Thymoglobulin pts 33d vs. non-Thymoglobulin pts 93d). Of 12 patients who developed detectable viral loads, 7 (58%) did so within 6 weeks of Tx. Peak EBV viral load ranged from 2,600 to 380,000 copies/ml; median 28,500 copies/ml (Thymoglobulin pts 26,000 vs. non-Thymoglobulin pts 47,000). Time to peak viral load was 32-1023 days, median 177 (Thymoglobulin pts 121d vs. non-Thymoglobulin pts 239d). Of the 3 patients who never developed a measurable viral load, none had pre-transfusion confirmation of donor seropositive status. Seronegative recipients with seronegative donors have not demonstrated early (first six weeks) viral loads, and screening of filtered blood products are also EBV-PCR negative suggesting that the loads observed in this study were not due to blood product use during cardiopulmonary bypass. Conclusions: EBV seronegative pediatric Tx recipients receiving hearts from seropositive donors experience very early EBV infection with evidence of viremia often within 4-6 weeks of Tx. Induction therapy may be associated with earlier viremia. EBV-PCR screening more frequently than monthly maybe indicated early after Tx in this population if any form of experimental / therapeutic intervention is planned at the time of primary EBV infection. Tumor necrosis factor (TNF) plays a crucial role in the pathogenesis of graft-vs-host disease (GVHD), the major cause of treatment-related mortality (TRM) after allogeneic bone marrow transplantation (BMT). We tested the hypothesis that early rises in TNF (on day 7 following BMT) predict the development of significant GVHD and TRM. Ratios of soluble TNF receptor 1 (TNFR1) levels (day 7 level/pre-BMT level) was used as a surrogate marker for TNF in 440 myeloablative allogeneic BMT pts with a median age of 42y (range 0-65y)....
Children's Mercy Hospitals and Clinics, Kansas City, Missouri, U.S.A.Drug biotransformation can be altered by diet in adults resulting in drug accumulation and toxicity, or in some cases, enhanced elimination. The cytochrome P450 enzymes (CYPs) are a super family of heme-containing phase I enzymes responsible for biotransformation of a significant number of commonly used pharmacologic agents and a large array of endogenous substrates. Previous studies suggest that drug metabolism by CYPs differs between breast-fed and formula-fed infants. The effect of infant diet on the development of functional CYP activity is assessed in this report. Oral doses of caffeine and dextromethorphan were used as pharmacologic probes to track CYP enzyme activity in neonates seen at 6 visits over their first 6 months of life. The caffeine elimination rate constant (k e ) was determined from serum caffeine levels obtained on alternating visits. At all visits, levels of caffeine, dextromethorphan, and their respective metabolites were determined by HPLC in urine samples collected over a 24 hr post-dose period. The serum caffeine k e of infants at their first study visit (2 weeks post-natal age) was unrelated to post-conceptional age. Caffeine elimination was low in infants at this first visit and displayed a significant positive linear correlation with increasing post-natal age (k e ϭ .004 (Age [weeks]) ϩ .001; pϽ0.001). Caffeine k e increased faster in formula-fed infants (slope ϭ .005 95%CI: 0.004, 0.006) than in breast-fed infants (slope ϭ .002 95%CI: 0.001, 0.002) (pϽ0.001) concomitant with increased conversion of caffeine to 3-demethylated metabolites. In contrast, breast feeding significantly increased the urinary fractional molar recovery of 3-methylxanthine (fr3X) [(fr3X) ϭ .004 Age [weeks] ϩ .016; pϽ 0.01] suggesting that this feeding modality produces a relative shunt in metabolism towards 7-demethylated metabolites. Dextromethorphan metabolism, assessed as the fractional molar recovery of 3-hydroxymorphinan (fr3HM), showed a similar marked increase with postnatal age [(fr3HM) ϭ .014 Age [weeks] ϩ .203; pϽ 0.001] that did not differ between diets. The maturation of caffeine elimination does not appear to begin until after birth. Formula feeding appears to accelerate the development of caffeine metabolism but not dextromethorphan. There may be specific ligand(s) unique to infant formula or human breastmilk that modify the developmental regulation of CYP1A gene expression and/or activity. Dietary modification of CYP activity may alter drug bioavailability and increase exposure to modified xenobiotics or endogenous metabolites from a very early age. IDENTIFYING THE MOUSE GENE RESPONSIBLE FOR CONGENITAL PROGRESSIVE HYDRONEPHROSIS (CPH).PD Brophy, J Clarke, RM Raymond Jr. University of Michigan Department of Pediatrics, Ann Arbor, MI.Obstructive uropathy is the leading cause of chronic renal failure and ESRD in children. Understanding the genetic and molecular control of urinary tract development is critical for making an impact o...
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