Association of cytomegalovirus genotype with graft rejection after liver transplantation

BACKGROUND: The envelope glycoprotein gB of human cytomegalovirus (CMV) occurs as one of four main genotypes. Some previous studies have proposed a relationship of CMV gB genotype to the frequency of symptomatic infection and to clinical outcomes in both transplant and human immunodeficiency virus-infected populations. Our aim was to define the distribution of CMV gB genotypes and the impact on acute cellular rejection and graft/patient survival after orthotopic liver transplantation (OLT). METHODS: Between October 1988 and December 1996, 325 patients underwent cyclosporine-based OLT at our center. CMV infection was surveyed prospectively and defined as viral isolation from blood or urine; 53 (16%) patients had detectable CMV. Isolates were genotyped by polymerase chain reaction amplification and restriction digest analysis. RESULTS: The distribution of CMV genotypes was: gB1, 19 (36%) patients; gB2, 15 (28%) patients; gB3, 13 (24%) patients; and gB4, 4 (8%) patients. Two patients (4%) had mixed infection (1 + 3, 1 + 4). Age, preOLT diagnosis, use of ganciclovir prophylaxis, basal immunosuppression, mean number of HLA donor/recipient mismatches, and United Network of Organ Sharing status were comparable among patients with different genotypes. Patients with gBl had a significantly higher mean number of acute rejection episodes (1.52+0.30 vs. 0.67+0.22; P=0.027). However, there was no difference in rejection severity, including OKT3 usage or FK506 conversion, or development of chronic rejection among patients with different genotypes. The gB genotype did not affect the development of symptomatic or tissue-invasive CMV disease, detected in 15 patients. Actuarial rates of patient (odds ratio [OR] 3.0; confidence interval [CI] 1.49-6.0) and graft (OR 2.57; CI 1.25-5.22) survival were significantly diminished in the group with CMV infection versus those without CMV (P<0.0001 for both), but there was no association with CMV genotype. CONCLUSIONS: (1) Patients with CMV infection had significantly reduced patient and graft survival rates at 1 and 5 years after OLT as compared with OLT recipients without CMV infection. (2) CMV genotype gB1 was associated with a higher mean number of acute rejection episodes.     

Defining the outcome of immunosuppression withdrawal after liver transplantation

Successful immunosuppression withdrawal should benefit the natural history of organ transplantation patients. To identify the clinical hazards of removing drug treatment and possible characteristics that predict a favorable outcome in long-term liver recipients, immunosuppression was withdrawn completely and the clinicopathological outcome documented in 18 liver recipients. Indication for transplantation, HLA matching, early rejection history, and presence of microchimerism were examined as predictors of outcome. Chimerism was determined by polymerase chain reaction-based examination for donor-specific HLA-DRB1 alleles and Y-gene-specific nucleotide sequences. At 3 years, 5 patients (28%) remained completely off immunosuppression; 12 patients (67%) experienced histological graft changes: acute rejection in 4, portal tract inflammation/hepatitis in 7, and necrosis in 1. Hepatitis B or C viral infections did not account for the nonrejection patterns. Unmasking of systemic disorders occurred. Chimerism, demonstrated in 7 patients (39%), with skin the optimal tissue, was not associated with tolerance. Parameters associated with successful drug withdrawal were transplantation for non-immune-mediated liver disorders, fewer donor-recipient HLA A, B, and DR mismatches, and a low incidence of early rejection. Immunosuppression withdrawal is a feasible option in a proportion of selected liver recipients, but identification of tolerant patients remains imprecise.     

C-reactive protein in the monitoring of acute rejection after heart transplantation

OBJECTIVE: To measure short duration sounds (L(PEAK)) in the neonatal intensive care unit and describe their intensity, incidence, and periodicity in relationship to activities within the unit. STUDY DESIGN: We measured 1-minute L(PEAK) at four locations within the intensive care unit, accumulating 48 hours of data for each weekday. RESULTS: Thirty-one percent of the L(PEAK) exceeded 90 dB. For further analysis, the data were transformed to the proportion exceeding 90 dB. These values varied significantly with day, week, location, and time of day. During physician rounds, there was a 16% relative increase in L(PEAK). CONCLUSION: These data demonstrate the intensity, incidence, and periodicity of short duration sounds in the intensive care nursery. Short duration sounds are known to affect the infant's physiological and behavioral states and should be addressed in future recommendations for sound control and reduction strategies.     

Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation

Purified native F1 antigen from Yersinia pestis was used to assess controlled-release vaccine delivery systems in poly(lactide-co-glycolide) (PLG) microparticles and liposomes. Antigen encapsulated in PLG microparticles induced high serum titres when injected i.p. in mice: mucosal IgA was also detected. Mice immunized with F1 in Alhydrogel or PLGs were protected against subcutaneous challenge with Y. pestis. F1 antigen surface-labelled onto liposome vesicles stimulated high serum titres in Balb/c mice and also induced a mucosal response: F1-labelled liposomes protected mice against challenge with up to 1 x 10(5) organisms. These findings indicate that a significant immune response is induced by immunizing with F1 formulated in PLGs and liposomes and that protection was achieved after only one dose.     

Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation

A novel complex mutation consisting of a small deletion/insertion (3958del5ins4) was found in the breast cancer-1 gene (BRCA-1) in three unrelated French breast and/or ovarian cancer families. These mutations occurred at the same nucleotide position of the 3' end of exon 11. The wild-type sequence, CTCAG, was deleted and replaced by AGGC in the three families. The consequence is the generation of a stop codon, TAG, resulting in a truncated protein. We propose two different mechanisms to explain the generation of this complex mutation: (i) the simultaneous occurrence of a deletion and an insertion in a stem-loop structure and (ii) the abortive integration of a human transposable element (Tigger 1) that deleted 5 nucleotides and inserted a 4-nucleotide "scar", corresponding to the 5' extremity of the transposon.     

Survival after heart transplantation without regular immunosuppression

Seventy renal allograft biopsies were done in 31 patients, routinely at 1, 2, and 3 months posttransplant, and as clinically indicated, using an automated biopsy "gun." The histological diagnosis was made according to the Banff schema, which emphasizes tubulitis and vascular inflammation over mononuclear cell infiltration. Fifty-three biopsies satisfied histological inclusion criteria. Twenty-nine biopsies were obtained from stable patients, defined as those in whom serum creatinine had changed < 10% in 2 weeks, and in whom immunosuppression (cyclosporine, azathioprine, and prednisone) had not been increased in that interval. Of these biopsies, 30% (9/29) showed rejection, which could not have been predicted from pretransplant (HLA mismatch, panel-reactive antibody titer) or posttransplant (cyclosporine and serum interleukin 2 receptor levels) variables. The significance of these early subclinical rejection episodes is unknown, and their effects on long-term graft histology and function are being examined in a controlled study.     

Heart rate variability as an assessment of acute rejection after heart transplantation

BACKGROUND: Orthotopic heart transplantation is currently a widely accepted treatment for end-stage heart disease. Early detection and adequate therapy of acute rejection increases the survival rate. Currently, the most reliable technique for the detection of acute cardiac rejection (ACR) is endomyocardial biopsy (EMB), which is an invasive procedure with some intrinsic problems. The purpose of this study was to assess heart rate variability (HRV) as a noninvasive procedure for frequent monitoring of ACR. METHODS: Six consecutive orthotopic cardiac transplant recipients were prospectively recruited into this study. The follow-up periods ranged from seven to 359 days (median; 146 days). A precordial electrocardiograph (ECG) of 288 seconds was recorded at 5:00 PM before the patient underwent EMB. The results from the frequency domain analysis of the ECG signals were evaluated to correlate with the findings from EMB. RESULTS: Of 48 EMBs, 42 (87.5%) showed no evidence of rejection, four showed mild focal ACR (EMB grade 1A), one mild diffuse ACR (1B) and one moderate plurifocal ACR (3A). There was no moderate focal ACR (2), severe diffuse ACR (3B) or severe ACR (4). Correlation between ACR (3A) and a significant increase in HRV with a corresponding 'broad-band' or bell-shaped pattern on the power spectrum was noted. CONCLUSIONS: Our study in consecutive cardiac transplant recipients indicates that the changes in HRV provide clinicians with a new concept for heart transplant monitoring. Further study is needed to verify clinical utility.     

Lamivudine treatment for acute hepatitis B after liver transplantation

Although epidemiological and experimental studies indicate a strong relationship between different dietary fats and risk of colon cancer, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. Activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is well established that the transforming ability of ras-p21 depends on its correct localization in plasma membrane. We have previously demonstrated that ingestion of a relatively higher amount of dietary fish oil leads to reduced plasma membrane levels of ras-p21 with concomitant increase in its cytoplasmic contents during the promotion and progression phases of chemically-induced colon tumorigenesis. In this follow-up experiment, we have found that intake of a high amount of corn oil, one of the most widely used fats in the American diet, enhances the expression of farnesyl protein transferase (FPTase). This enzyme catalyses farnesylation of ras precursors in a critical step during post-translational modification of ras oncoproteins, thereby enabling their anchorage to plasma membrane. In contrast, consumption of high amounts of fish oil, which is rich in omega-3 polyunsaturated fatty acids, reduces the levels of FPTase expression, thus inhibiting post-translational processing of ras precursors resulting in decreased ras function both in colonic mucosa as well as in colon tumors. These results correlate with increased incidence and multiplicity of grossly visibly colon tumors in carcinogen-treated animals fed a high corn oil diet versus decreased incidence and multiplicity of colon tumors in their counterparts fed the high fish oil diet. This dietary inhibition of FPTase may have a practical chemopreventive potential.     

Reversal of early acute rejection with increased doses of tacrolimus in liver transplantation: a pilot study

BACKGROUND: In this pilot study, we present the results of treatment of early (3 months after liver transplantation) acute rejection episodes by increasing only the tacrolimus doses. METHODS: Ten patients who received tacrolimus as primary treatment experienced acute mild (one case), moderate (four cases), or severe (five cases) rejection episodes. Tacrolimus dosing was increased 1-2 mg every 1 or 2 days until hepatic enzymes started to improve. Steroid basic daily doses were kept unchanged. RESULTS: With the daily dose of tacrolimus increased by a median 1.89-fold (range: 1.2-5), alanine aminotransferase, bilirubin, and gamma-glutamyltranspeptidase levels rapidly reached normal values within the first month. During a median follow-up time of 19.5 months (range: 14-24), none of the 10 patients died or lost their graft. Control liver biopsies were done 13.5 months (range: 7-19) after rejection episode in all patients, and none demonstrated evidence of rejection or sequela. CONCLUSION: This pilot study suggests that increasing tacrolimus dosage could be considered as treatment against early acute rejection episodes including the severe grade.