(1/1093) Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued?
Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients. (+info)
(2/1093) Merkel cell carcinoma and melanoma: etiological similarities and differences.
Merkel cell carcinoma (MCC) of the skin and cutaneous malignant melanoma can now be compared epidemiologically through the use of population-based data not previously available for MCC. The results may provide new clues to etiology. In this study, United States data covered by the Surveillance, Epidemiology, and End Results (SEER) Program were from nine areas of the United States (approximately 10% of the population). In 1986-1994, 425 cases of MCC were registered. The annual age-adjusted incidence per 100,000 of MCC was 0.23 for whites and 0.01 for blacks; among whites, the ratio of melanoma to MCC was approximately 65 to 1. Only 5% of MCC occurred before age 50, unlike the lifelong risk of nodular and superficial spreading melanoma. Regional incidence rates of both cancers increased similarly with increasing sun exposure as measured by the UVB solar index. The most sun-exposed anatomical site, the face, was the location of 36% of MCC but only 14% of melanoma. Both cancers increased in frequency and aggressiveness after immunosuppression and organ transplantation (36 cases from the Cincinnati Transplant Tumor registry and 12 from published case reports) and after B-cell neoplasia (5 cases in this study; 13 from case series in the literature). The SEER data contained reports of six patients with both types of cancer; 5 melanomas before the diagnosis of MCC and 1 after diagnosis. MCC and melanoma are similarly related to sun exposure and immunosuppression, but they differ markedly from one another in their distributions by age, race, and anatomical site, especially the face. (+info)
(3/1093) Clinical significance of expression of human cytomegalovirus pp67 late transcript in heart, lung, and bone marrow transplant recipients as determined by nucleic acid sequence-based amplification.
Human cytomegalovirus (HCMV) infection was monitored retrospectively by qualitative determination of pp67 mRNA (a late viral transcript) by nucleic acid sequence-based amplification (NASBA) in a series of 50 transplant recipients, including 26 solid-organ (11 heart and 15 lung) transplant recipients (SOTRs) and 24 bone marrow transplant recipients (BMTRs). NASBA results were compared with those obtained by prospective quantitation of HCMV viremia and antigenemia and retrospective quantitation of DNA in leukocytes (leukoDNAemia). On the whole, 29 patients were NASBA positive, whereas 10 were NASBA negative, and the blood of 11 patients remained HCMV negative. NASBA detected HCMV infection before quantitation of viremia did but after quantitation of leukoDNAemia and antigenemia did. In NASBA-positive blood samples, median levels of viremia, antigenemia, and leukoDNAemia were significantly higher than the relevant levels detected in NASBA-negative HCMV-positive blood samples. By using the quantitation of leukoDNAemia as the "gold standard," the analytical sensitivity (47.3%), as well as the negative predictive value (68. 3%), of NASBA for the diagnosis of HCMV infection intermediate between that of antigenemia quantitation (analytical sensitivity, 72. 3%) and that of viremia quantitation (analytical sensitivity, 28.7%), while the specificity and the positive predictive value were high (90 to 100%). However, with respect to the clinically relevant antigenemia cutoff of >/=100 used in this study for the initiation of preemptive therapy in SOTRs with reactivated HCMV infection, the clinical sensitivity of NASBA reached 100%, with a specificity of 68. 9%. Upon the initiation of antigenemia quantitation-guided treatment, the actual median antigenemia level was 158 (range, 124 to 580) in SOTRs who had reactivated infection and who presented with NASBA positivity 3.5 +/- 2.6 days in advance and 13.5 (range, 1 to 270) in the group that included BMTRs and SOTRs who had primary infection (in whom treatment was initiated upon the first confirmation of detection of HCMV in blood) and who presented with NASBA positivity 2.0 +/- 5.1 days later. Following antiviral treatment, the durations of the presence of antigenemia and pp67 mRNA in blood were found to be similar. In conclusion, monitoring of the expression of HCMV pp67 mRNA appears to be a promising, well-standardized tool for determination of the need for the initiation and termination of preemptive therapy. Its overall clinical impact should be analyzed in future prospective studies. (+info)
(4/1093) Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders.
Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detected at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of cell-free EBV DNA in serum from solid-organ transplant recipients as a marker for PTLD. Five of 6 transplant recipients with histopathologically documented PTLD had EBV DNA detected in serum at the time of diagnosis (sensitivity = 83%), compared with 0 of 16 matched transplant recipients without PTLD (specificity = 100%) (P < 0.001 [Fisher's exact test]). Furthermore, EBV DNA was detected in serum 8 and 52 months prior to the diagnosis of PTLD in two of three patients for whom stored sera were analyzed. Detection of EBV DNA in serum appears to be a useful marker for the early detection of PTLD in solid-organ transplant recipients. Further studies to define the role of such assays in evaluating solid-organ transplant patients at risk for PTLD are warranted. (+info)
(5/1093) Cytokine mRNA profiles in Epstein-Barr virus-associated post-transplant lymphoproliferative disorders.
Cytokine mRNA patterns were analyzed in 11 post-transplant lymphoproliferative disorder (PTLD) specimens using qualitative reverse-transcriptase polymerase chain reaction (RT-PCR). In each case, a pattern of IL2-, IFN gamma-, IL4+, IL10+ was seen. A similar pattern was observed in a spleen sample from 1 patient with contemporaneous PTLD elsewhere. Semiquantitative RT-PCR for cytokine message was performed using RNA from bronchoalveolar lavage (BAL) specimens obtained from 2 patients with pulmonary PTLD. In both cases, IL4 message predominated. Reduction of message coincided with resolution of the tumors. The pattern differed from that seen in 1 patient with acute pulmonary rejection, in which RT-PCR of BAL cells showed predominance of IL6 and IFN gamma. We conclude that at least some PTLDs exist within a T-helper cell type 2 (Th2)-like cytokine microenvironment. The presence of a similar mRNA pattern in an extratumoral specimen at the time of PTLD suggests that it may reflect a systemic phenomenon. Disappearance of this pattern following PTLD resolution indicates its dynamic nature and is consistent with the hypothesis that specific cytokines contribute to the development of PTLDs. (+info)
(6/1093) Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil.
1. Mycophenolic acid (MPA), is primarily metabolized in the liver to 7-O-MPA-beta-glucuronide (MPAG). Using RP-h.p.l.c. we observed three further MPA metabolites, M-1, M-2, M-3, in plasma of transplant recipients on MMF therapy. To obtain information on the structure and source of these metabolites: (A) h.p.l.c. fractions containing either metabolite or MPA were collected and analysed by tandem mass spectrometry; (B) the metabolism of MPA was studied in human liver microsomes in the presence of UDP-glucuronic acid, UDP-glucose or NADPH; (C) hydrolysis of metabolites was investigated using beta-glucosidase, beta-glucuronidase or NaOH; (D) cross-reactivity of each metabolite was tested in an immunoassay for MPA (EMIT). 2. Mass spectrometry of M-1, M-2, MPA and MPAG in the negative ion mode revealed molecular ions of m/z 481, m/z 495, m/z 319 and m/z 495 respectively. 3. Incubation of microsomes with MPA and UDP-glucose produced M-1, with MPA and UDP-glucuronic acid MPAG and M-2 were formed, while with MPA and NADPH, M-3 was observed. 4. Beta-Glucosidase hydrolysed M-1 completely. Beta-Glucuronidase treatment led to a complete disappearance of MPAG whereas the amount of M-2 was reduced by approximately 30%. Only M-2 was labile to alkaline treatment. 5. M-2 and MPA but not M-1 and MPAG cross-reacted in the EMIT assay. 6. These results suggest that: (i) M-1 is the 7-OH glucose conjugate of MPA; (ii) M-2 is the acyl glucuronide conjugate of MPA; (iii) M-3 is derived from the hepatic CYP450 system. (+info)
(7/1093) Epidemiology of visceral mycoses: analysis of data in annual of the pathological autopsy cases in Japan.
The data on visceral mycoses that had been reported in the Annual of the Pathological Autopsy Cases in Japan from 1969 to 1994 by the Japanese Society of Pathology were analyzed epidemiologically. The frequency of visceral mycoses among the annual total number of pathological autopsy cases increased noticeably from 1.60% in 1969 to a peak of 4.66% in 1990. Among them, the incidences of candidiasis and aspergillosis increased the most. After 1990, however, the frequency of visceral mycoses decreased gradually. Until 1989, the predominant causative agent was Candida, followed in order by Aspergillus and Cryptococcus. Although the rate of candidiasis decreased by degrees from 1990, the rate of aspergillosis increased up to and then surpassed that of candidiasis in 1991. Leukemia was the major disease underlying the visceral mycoses, followed by solid cancers and other blood and hematopoietic system diseases. Severe mycotic infection has increased over the reported 25-year period, from 6.6% of the total visceral mycosis cases in 1969 to 71% in 1994. The reasons for this decrease of candidiasis combined with an increase of aspergillosis or of severe mycotic infection might be that (i) nonsevere (not disseminated) infections were excluded from the case totals, since they have become controllable by antifungal drugs such as fluconazole, but (ii) the available antifungal drugs were not efficacious against severe infections such as pulmonary aspergillosis, and (iii) the number of patients living longer in an immunocompromised state had increased because of developments in chemotherapy and progress in medical care. (+info)
(8/1093) N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats.
BACKGROUND: Cyclosporin (CsA) has played an important role in the improvement of solid-organ transplant patients and graft survival. However, nephrotoxicity due to CsA remains an important clinical challenge. The renal toxicity of CsA is attributed to reduced renal blood flow which leads to hypoxia reoxygenation injury accompanied by excessive generation of oxygen-derived free radicals (ODFR). N-acetyl-L-cysteine (NAC) is a highly potent antioxidant that has been shown to reduce ODFR injury. In this study an attempt was made to assess the effect of NAC on CsA-induced lipid peroxidation and nephrotoxicity. METHODS: Adult Sprague-Dawley rats were treated orally with CsA (25 and 50 mg/kg) alone and in combination with different doses of NAC (10, 20 and 40 mg/kg) for a period of 3 weeks. Twenty-four hours after the last treatment, animals were sacrificed and blood was analysed for blood urea nitrogen (BUN) and serum creatinine (SCr), and kidney samples were analysed for lipid hydroperoxides, conjugated dienes and glutathione, and histopathological changes. RESULTS: Treatment of rats with CsA produced a significant increase in BUN and SCr level and histological abnormalities. CsA-induced impairment of renal toxicity was accompanied by significant increase in renal oxidative stress. NAC treatment significantly protected animals against CsA-induced structural and functional impairment of kidney. CONCLUSIONS: CsA-induced nephrotoxicity was significantly attenuated by NAC. This study clearly suggests the role of oxidative stress in the pathogenesis of CsA-induced nephrotoxicity. Concomitant use of antioxidants such as NAC to minimize CsA-induced nephrotoxicity in humans warrant further studies. (+info)