Graft survival in a rhesus renal transplant model after immunotoxin-mediated T-cell depletion is enhanced by mycophenolate and steroids.

BACKGROUND: Anti-CD3 immunotoxin (IT), a T-cell-depleting agent, prolongs survival of renal allografts in a rhesus monkey model without the need for long-term immunosuppression. In this study we sought to further prolong allograft survival by giving short-term conventional immunosuppression simultaneous with IT administration. METHODS: MHC class II mismatched, juvenile rhesus monkeys were paired as donor and recipient for renal transplantation. Recipients received two to three daily doses of IT starting on the day of transplantation. Additional immunosuppression was given for no more than 60 days. Graft function was monitored by serum creatinine and renal biopsies. Flow cytometry was used to monitor T-cell recovery. RESULTS: Graft survival time (GST) in animals receiving IT was prolonged compared with controls with 50% of IT-treated monkeys surviving >100 days. Animals treated with IT plus mycophenolate mofetil (MMF) and steroids had significantly enhanced GST (mean GST, 305 days) compared with those treated with IT alone (mean GST, 94 days). In contrast, addition of cyclosporine or 40-O-[2-Hydroxyethyl]rapamycin did not significantly increase graft survival time. A comparison among animals from all treatment groups with short (<100 days) and long (>100 days) GST demonstrated that those with the shorter GST had a higher blood T-cell count 2 weeks after transplantation. Full recovery of CD4+ T cells required longer than 6 months. CONCLUSIONS: A combination with MMF and steroids given for 4 days after renal allograft transplantation significantly increases GST in IT-treated monkeys. We hypothesize that MMF and steroids suppress the initial T-cell activation mediated by IT.

Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients.

BACKGROUND: Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival. METHODS: Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection. RESULTS: Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy. CONCLUSIONS: Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.

Nurse practitioners' effectiveness in NICU.

The effectiveness of Neonatal Nurse Practitioners (NNPs) in a Level III Neonatal Intensive Care Unit (NICU) was evaluated by using a retrospective medical records review. Two groups of infants received care in a Transitional Care Unit (TCU), one by house officers and the second cared for by NNPs. Medical diagnoses, lengths of stay, hospital charges, discharge/transfer disposition and hospital readmissions were studied. No differences were found in DRG codes, discharge disposition, hospital readmission or number of infants transferred from TCU to NICU because of deteriorating condition. Though the infants cared for by the NNPs had significantly lower birth weight and lower gestational age, they averaged 2.4 fewer days in the hospital and $3,491 less in total hospital charges than the group cared for by house officers. This study confirms that NNPs can provide care comparable to house officers in a Level III NICU and be more cost effective.

Meconium analysis for improved identification of infants exposed to cocaine in utero.

We screened anonymously all mothers and infants born during a 3 1/2-month period to determine the prevalence of intrapartum cocaine use, test the maternal characteristics that are specific predictors of intrauterine cocaine exposure (IUCE), and compare the sensitivity of infant urine versus meconium samples for identification of IUCE. Of 1237 live births during the study period, a sample was obtained from 1201 mother-infant pairs. The overall prevalence of documented intrapartum cocaine exposure was 66 (5.5%) of 1201 pairs. Previously developed drug screening guidelines had a sensitivity of 89% for detecting IUCE in infants. Direct comparisons of samples from the same mother-infant pair revealed that there were no cases in which cocaine was found in infant urine but not in meconium; however, infant urine testing missed 25% of the infants who had positive findings in meconium. We conclude that (1) meconium testing was more likely than urine testing to identify an infant with IUCE, detecting an additional 33%; (2) there was significant maternal cocaine use (5.5%) in a teaching hospital with a mixed patient population; (3) maternal characteristics known to identify infants at risk of having IUCE were useful in our population; and (4) IUCE of neonates admitted to the neonatal intensive care unit was more common than that of infants admitted to the regular newborn nursery.

The phonetic interpretation of tone in Igbo.

This article presents a preliminary study of the phonetic interpretation of tone in Igbo, a Kwa language of southeastern Nigeria. The experimental method varies the speaker's pitch range orthogonally with variation in tonal material, and fits a model to measurements of maxima and minima in the resulting F0 contour. A new interpretation of downstep is proposed as a result.

Smoking-attributable mortality, years of potential life lost, and direct health care costs for Puerto Rico, 1983.

The authors report the impact of smoking upon health in Puerto Rico for the year 1983. Using a microcomputer spread-sheet program that calculates smoking-attributable disease impact, they estimated that 2,468 deaths were attributable to smoking. This represented 11.5% of all deaths on the island in 1983 and resulted in approximately 19,445 years of potential life lost (YPLL). It appears that cigarette smoking caused US+55.9 million in direct health care expenditures for Puerto Rico in 1983, an amount equal to 10% of the island's yearly expenditures on health. Calculations such as these demonstrate the enormous disease impact of smoking and may assist policy-makers in planning prevention and intervention activities, both in Puerto Rico and elsewhere in Latin America.

Enhancement by various cytokines or 2-beta-mercaptoethanol of Ia antigen expression on Langerhans cells in skin from normal aged and young mice. Effect of cyclosporine A.

The number of Ia+ Langerhans cells (LC) in skin from aged (16- to 18-mo old) BALB/c mice is approximately 40% lower than in skin from young (2- to 3-mo old) mice. Overnight incubation at 37 degrees C with a variety of cytokines, including IL-1, IL-2, IL-3, IL-4, IL-6, TNF-alpha, IFN-gamma, and granulocyte/macrophage-CSF, causes a significant increase in the Ia expression on LC and raises the number of Ia+ cells by at least 300/mm2 in skin from both young and old mice. At 1 to 5 x 10(-5) M, 2-ME has a similar effect. The percentage increment in Ia+ cells is much higher for skin from aged mice than from young mice, particularly with IL-3, which appears to reconstitute the number of Ia+ LC in skin from aged mice to that of IL-3 exposed skin from young mice. Under the incubation conditions of our experiments, neither keratinocytes nor Thy-1+ dendritic cells acquire Ia Ag. Addition of 10 micrograms/ml cyclosporine A to the medium abolishes the effect of 2-ME and of all of the cytokines except IL-2 and IL-6. These results demonstrate the presence of a significant population of Ia- LC in the epidermis of both young and aged mice. It is suggested that epidermal production of cytokines may be of importance in the maintenance of constitutive Ia expression on LC. The possible interaction between keratinocytes and LC and the effect of aging on this process are discussed.

Relative lack of systemic effects of mometasone furoate on Langerhans cells of mice after topical administration as compared with other glucocorticosteroids.

The effects of topically applied mometasone furoate were compared with those of other glucocorticosteroids, in particular fluocinolone acetonide, in assays of murine epidermal Ia+ Langerhans cell density. No evidence of systemic effects, as determined by a decline in the density of Ia+ LC in distant sites, was detected after local topical applications (5 times a week) of mometasone furoate 0.001% for periods of up to 3 weeks. Other steroids, even in such very low concentrations, and mometasone furoate in higher concentrations, produced systemic effects on Ia+ LC when used for longer than 5 d. The recovery time of Ia+ Langerhans cells is significantly shorter after application of mometasone furoate than after fluocinolone acetonide. However, with both compounds, recovery occurred more rapidly after 3 weeks than after a 1- or 2-week interval of compound administration.