Interstitial and vascular pancreas rejection in relation to graft survival

To examine the incidence of interstitial and vascular rejection in pancreas allografts and its impact on graft survival, we studied 36 percutaneous pancreas biopsies and 10 pancreas transplantectomy specimens from 32 patients who had undergone simultaneous pancreas-kidney transplantation. Interstitial rejection (IR) was predominantly found in the biopsies, while vascular rejection (VR) was most prominent in the transplantectomies. Pancreas graft survival was significantly decreased for pancreas grafts that had suffered from vascular rejection when compared to those with only interstitial rejection. Potential rejection markers, i. e., serum amylase, glucose, creatinine, and urinary amylase, did not correlate with histological signs of rejection, although increased levels of serum amylase were, in all but one case, associated with rejection.We conclude that a percutaneous pancreas biopsy remains the most reliable method to determine pancreas rejection, and that by distinguishing between IR andVR, a pancreas biopsy may provide important diagnostic as well as prognostic information. Received: 6 March 1997 Received after revision: 5 June 1997 Accepted: 30 June 1997     

Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

Patient survival after renal transplantation; more than 25 years follow-up

Background: The determinators of patient survival after renal transplantation are incompletely known, and conflicting results hae been reported. This may have been influenced by time-related changes in patients selection, post-transplantation management and immunosuppressive regimens. This study was performed to evaluate in recipients of a first renal transplant the effect of patient characteristics, transplantation era, and the immunosuppressive regimen on patient survival. Method: We studied data from the Leiden Renal Transplant Database of all first renal transplantations performed between 1966 and 1994 in Leiden, the Netherlands. The effect of the following parameters on mortality was investigated: era of transplantation, sex, age at transplantation, cause of renal failure, immunosuppressive regimen, type and duration of pretransplantation dialysis, hypertension, diabetes mellitus, and smoking. In addition we analysed the causes of death. Results were expressed as crude mortality rates, relative risks of mortality, and standardized mortality ratios as compared with death rates in the Dutch population. Results: The analysis comprised 86 living donor transplant recipients and 916 cadaver transplant recipients. After adjustment for age and sex, the relative risk of morality for living donor transplant recipients compared with cadaver transplant recipients was 0.5 (95% CI 0.2 to 10.3, P=0.06). In the first cadaver kidney transplant recipients the risk of first-year mortality improved significantly with time, which coincided with the introduction of cyclosporin. The risk of mortality after the first year was higher in patients aged over 40 years at transplantation, men, smokers, and in the presence of hypertension or diabetes, but the effect of individual factors on mortality was small. We found no effect of the type of pretransplantation dialysis or the duration of pretransplantation haemodialysis on post-transplantation mortality. The standardized mortality ratio for recipients of first renal transplants was 14 times the population average in the first year after transplantation and was still four times in the remaining years. Conclusion: In the present study, time-related changes in patient management were responsible for improved patient survival in the first year after transplantation during the study period. Many individual factors contributed moderately to the risk of mortality after the first year. Compared to the general population the mortality rate of renal transplant recipients was significantly higher during the whole follow-up period.     

Magnetic resonance relaxation times of normal tissue in the course of chemotherapy: a study in patients with bone sarcoma

To study the effect of chemotherapy on normal fat, skeletal muscle, and bone marrow, T1 and T2 relaxation times were measured in 15 patients with bone sarcoma before and after each cycle of preoperative chemotherapy. A section plane containing the tumor and if possible the nonaffected extremity was imaged with combined multiecho spin echo and inversion recovery pulse sequences. T1 and T2 relaxation times were calculated in the normal-appearing tissues. Although some variation was found in the values in the individual patient and between patients, no systematic changes of relaxation times of fat, muscle, or bone marrow occurred in the course of treatment. We conclude that the chemotherapy used in bone sarcoma has no effect on relaxation times of normal fat, muscle, and bone marrow, and that therefore these tissues may serve as a reference for the signal intensity of tumor.     

The role of quinone reductase (NQO1) and quinone chemistry in quercetin cytotoxicity.

The effects of quercetin on viability and proliferation of Chinese Hamster Ovary (CHO) cells and CHO cells overexpressing human quinone reductase (CHO+NQO1) were studied to investigate the involvement of the pro-oxidant quinone chemistry of quercetin. The toxicity of menadione was significantly reduced in CHO+NQO1 cells compared to wild-type CHO cells, validating the NQO1-overexpression in the CHO+NQO1 transfectant. Quercetin inhibited the proliferation of wild-type CHO and CHO+NQO1 cells to a similar extent without affecting cell viability, indicating that NQO1 enrichment of CHO cells did not provide increased protection. On the other hand, inhibition of NQO1 in both types of cells by dicoumarol significantly potentiated the inhibitory effect of quercetin on cell proliferation, revealing the role of NQO1 in cellular protection against quercetin. Altogether, these results can be explained by the hypothesis that both wild-type CHO and CHO+NQO1 cells contain sufficient NQO1 activity for optimal protection against the pro-oxidant effect of quercetin on cell proliferation. The results also point at a cellular NQO1 threshold for optimal protection against quercetin. This NQO1 threshold seems to be in the range of NQO1 activities already present in various tissues.     

Taking anti-neutrophil cytoplasmic antibody (ANCA) testing beyond the limits.

The application of anti-neutrophil cytoplasmic antibody (ANCA)testing has received much interest since ANCA were discovered[1] and since they were reported to be useful in both the diagnosisand monitoring of disease activity in Wegener's granulomatosis(WG) [2]. Although there is little doubt that the recognitionof the association between the presence of ANCA and active vasculitishas had a very positive influence on research on the pathogenesisand treatment of ANCA-associated diseases (reviewed by Savage[3]), there are reasons to worry about the application of thisrecently gained knowledge in clinical practice. In this commentthe problems with the clinical application of ANCA tests arecategorized for the sake of clarity as (i) standardization problems,(ii) difficulties with application of the test in the appropriate