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C V Paya

Publications and source records attributed to C V Paya.

At least 91 records · Page 5Linked to original sources
PubMed1995

Pretransplantation assessment of the risk of lymphoproliferative disorder.

Posttransplantation lymphoproliferative disorder (PTLD) is an uncommon but often fatal complication of solid organ transplantation that occurs in approximately 3% of patients. To determine the relative importance and relationship of potential risk factors for PTLD before transplantation (i.e., Epstein-Barr virus [EBV] serostatus of the recipient and the cytomegalovirus [CMV] sero-status of the recipient and the potential donor) and the principal risk factor after transplantation (immunosuppression with antilymphocyte antibody), we analyzed the findings for the first 381 consecutive adult nonrenal transplant recipients seen at Mayo Clinic. In the absence of the other risk factors, the incidence rate of PTLD for EBV-seronegative recipients was 24 times higher (95% confidence interval [CI]: 6.2, 89) than that for EBV-seropositive recipients. The additional risk factors of therapy with OKT3 for rejection and CMV seromismatch (i.e., a negative recipient and a positive donor) each further amplified this risk four- to sixfold. Together, all three risk factors acted synergistically to increase the incidence rate of fatal and/or CNS PTLD by a factor of 654 (CI: 368, 1,162) compared with the low incidence rate (.458 cases per 100 person years) when none of these risk factors were present. Pretransplantation determination of recipient EBV and CMV serostatus can identify a subgroup of patients whose risk for severe PTLD may preclude transplantation.

Adult↗
PubMed1995

A prospective comparison of molecular diagnostic techniques for the early detection of cytomegalovirus in liver transplant recipients.

Forty-one consecutive liver transplant recipients were studied by polymerase chain reaction (PCR) of serum and peripheral blood mononuclear cells, reverse transcription (RT)-PCR of peripheral blood mononuclear cells, and viral blood culture for symptomatic cytomegalovirus (CMV) infection. The techniques were also used to predict the occurrence of CMV infection. For diagnosis of symptomatic CMV infection, the sensitivity and specificity of the different techniques were as follows: PCR of serum, 100% and 45%; RT-PCR, 25% and 97%; PCR of peripheral blood mononuclear cells, 83% and 35%; and blood culture, 83% and 86%, respectively. PCR of serum was positive in 83% of subjects with symptomatic infection before onset compared with 17% positive by blood culture. While viral blood culture was the best technique for the diagnosis of symptomatic CMV infection, PCR of serum was best at predicting the development of symptomatic CMV infection.

Cytomegalovirus↗
PubMed1995

OKT3 treatment for allograft rejection is a risk factor for cytomegalovirus disease in liver transplantation.

The role of OKT3 monoclonal antibody administration was studied as a risk factor for symptomatic cytomegalovirus (CMV) infection in 229 consecutive liver transplant recipients not receiving specific CMV prophylaxis. Twenty-six patients (11.4%) received OKT3 and 17 of them developed CMV infection, 11 (4.8%) being symptomatic. OKT3 use was a significant risk factor for symptomatic CMV infection by both univariate (relative risk [RR], 2.9; 95% confidence interval [CI], 1.5-5.8; P = .002) and multivariate time-dependent (RR, 3.4; 95% CI, 1.7-7.1; P = .001) analyses. A subgroup analysis revealed that OKT3 use was a significant risk factor for symptomatic CMV infection in CMV-seropositive but not seronegative recipients. OKT3 therapy for steroid-resistant rejection is a risk factor for symptomatic CMV infection in liver transplant recipients who are seropositive for CMV before transplantation. This group should be targeted for antiviral prophylaxis when OKT3 antirejection therapy is used.

Cytomegalovirus Infections↗
PubMed1995

Comparison of three methods for extraction of viral nucleic acids from blood cultures.

Reliable nucleic acid extraction techniques for blood specimens are required for the sensitive detection of viral DNA. Standardized procedures for processing blood specimens for the molecular detection of herpesviruses (cytomegalovirus [CMV], herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus [EBV]) have not been established. Three methods were used to extract DNA from blood specimens from healthy donors and asymptomatic immunocompromised patients: (i) IsoQuick treatment of whole blood, (ii) extraction of the peripheral blood leukocytes by lysis (lysis buffer and proteinase K), and (iii) extraction of peripheral blood leukocytes with phenol-chloroform (sodium docecyl sulfate solution and proteinase K). All blood specimens from 25 healthy blood donors were negative for CMV, herpes simplex virus and varicella-zoster virus nucleic acid sequences, regardless of the extraction method, while three samples (12%) extracted by the lysis technique were positive for EBV DNA. Of 25 blood samples from asymptomatic immunocompromised patients, CMV and EBV each were detected in nine specimens by lysis extraction, four each by IsoQuick and four (CMV) and six (EBV) by the phenol-chloroform method. Our results indicate that the lysis method is optimal for the detection of CMV and EBV DNA sequences by PCR from the leukocytic fraction of blood specimens. DNA of these viruses is frequently present in blood specimens from asymptomatic immunocompromised patients and occasionally from healthy donors.

Base Sequence↗
PubMed1995

Optimization of detection of cytomegalovirus viremia in transplantation recipients by shell vial assay.

Cytomegalovirus (CMV) viremia is a widely used laboratory marker of CMV disease following transplantation and is additionally used to trigger preemptive antiviral therapy. Despite this, the optimal method for diagnosing CMV viremia in transplantation recipients remains unknown. To determine the sampling frequency and blood volume required for the optimal diagnosis of viremia by shell vial assay, a prospective study of 46 viremic transplantation recipients was conducted. Blood specimens (2.5 and 5 ml) were collected twice, 3 h apart, at a median of 1.4 days (range, 1 to 3 days) after the triggering shell vial-positive blood had been collected. Considering a single 2.5-ml specimen, an average of only 40% of previously viremic patients had documented CMV in their blood: this increased to 50% when a second 2.5-ml sample of blood was collected 3 h later. The yields of two 2.5-ml versus two 5-ml samples were 50 versus 61%, respectively. Viremia as detected by shell vial assay is intermittent, and increasing the frequency and volume of blood sampling increases its diagnosis. These results have implications in diagnosis of CMV infection and its preemptive therapy.

Bone Marrow Transplantation↗
PubMed1995

Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus.

The mechanisms regulating human immunodeficiency virus (HIV) persistence in human monocytes/macrophages are partially understood. Persistent HIV infection of U937 monocytic cells results in NF-kappa B activation. Whether virus-induced NF-kappa B activation is a mechanism that favors continuous viral replication in macrophages remains unknown. To further delineate the molecular mechanisms involved in the activation of NF-kappa B in HIV-infected monocytes and macrophages, we have focused on the regulation of the I kappa B molecules. First, we show that persistent HIV infection results in the activation of NF-kappa B not only in monocytic cells but also in macrophages. In HIV-infected cells, I kappa B alpha protein levels are decreased secondary to enhanced protein degradation. This parallels the increased I kappa B alpha synthesis secondary to increased I kappa B alpha gene transcription, i.e., increased RNA and transcriptional activity of its promoter-enhancer. Another protein with I kappa B function, p105, is also modified in HIV-infected cells: p105 and p50 steady-state protein levels are increased as a result of increased synthesis and proteolytic processing of p105. Transcriptional activity of p105 is also increased in infected cells and is also mediated by NF-kappa B through a specific kappa B motif. These results demonstrate the existence of a triple autoregulatory loop in monocytes and macrophages involving HIV, p105 and p50, and MAD3, with the end result of persistent NF-kappa B activation and viral persistence. Furthermore, persistent HIV infection of monocytes and macrophages provides a useful model with which to study concomitant modifications of different I kappa B molecules.

Base Sequence↗
PubMed1995

LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha.

LMP-1, an Epstein-Barr virus membrane protein expressed during latent infection, has oncogenic properties, as judged from its ability to transform B lymphocytes and rodent fibroblasts. LMP-1 induces the expression of bcl2, an oncogene which protects cells from apoptosis, as well as of genes encoding other proteins involved in cell regulation and growth control. The mechanisms by which LMP-1 upregulates these proteins is unknown, but it is plausible that LMP-1 modifies signal transduction pathways that result in the activation of one or more transcription factors that ultimately regulate transcription of oncogenic genes. NF-kappa B, a transcription factor controlling the expression of genes involved in cell activation and growth control, has been shown to be activated by LMP-1. The mechanism(s) regulating this activation remains unknown. Our data indicate that increased NF-kappa B DNA binding and functional activity are present in B-lymphoid cells stably or transiently expressing LMP-1. I kappa B alpha is selectively modified in LMP-1-expressing B cells. A phosphorylated form of I kappa B alpha and increased protein turnover-degradation correlate with increased NF-kappa B nuclear translocation. This results in increased transcription of NF-kappa B-dependent-genes, including those encoding p105 and I kappa B alpha (MAD3). These results indicate that LMP-1 activates NF-kappa B in B-cell lines by targeting I kappa B alpha. Identification of the pathways activated by LMP-1 to result in posttranslational modifications of I kappa B alpha will aid in determining the role of this virus-host cell protein interaction in Epstein-Barr virus-mediated oncogenesis.

B-Lymphocytes↗
PubMed1994

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

The interleukin-2 (IL-2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus (FK-506). Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the FK-506- and CsA-sensitive enzyme required for TcR mediated activation of the IL-2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co-stimulus required to activate the IL-2 promoter elements IL-2A (which binds the factors OAP and Oct-1) and IL-2E (which binds NF-AT), and completely substitutes for the Ca2+ co-stimulus required to stimulate an NF-kappa B-dependent element. Calcineurin stimulates the NF-kappa B element by enhancing inactivation of I kappa B/MAD3, an inhibitor of NF-kappa B, thereby increasing the amount of nuclear NF-kappa B DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor.

Base Sequence↗
PubMed1994

Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients.

Infections due to nontuberculous mycobacteria (NTM) in solid-organ transplant recipients are infrequent but may be a major cause of morbidity. We describe four cases of NTM infection in solid-organ transplant recipients. The manifestations included a nodule secondary to Mycobacterium kansasii infection in a heart transplant recipient, a cutaneous lesion and a pulmonary nodule secondary to M. kansasii infection in a renal transplant recipient, tenosynovitis secondary to Mycobacterium chelonae infection in a renal transplant recipient, and cutaneous lesions secondary to M. chelonae infection in a liver transplant recipient. We also summarize previously reported cases of NTM infections in solid-organ transplant recipients; common manifestations of NTM infections in solid-organ transplant recipients include cutaneous lesions of the extremities, tenosynovitis, and joint infection. Histopathologic examination of aspirates or biopsy specimens from involved areas and staining and culture for mycobacteria are essential for diagnosis. Treatment of NTM infection most commonly involves surgery, reduction in doses of immunosuppressive medications, and/or therapy with antimycobacterial medications; these treatments are often associated with a good outcome.

Adult↗
PubMed1994

Detection of cytomegalovirus DNA in sera of liver transplant recipients.

We prospectively studied the utility of the amplification of cytomegalovirus (CMV) DNA in the sera of liver transplant recipients in order to predict symptomatic CMV infection, thus enabling preemptive therapy with antiviral agents. Serum samples obtained at biweekly intervals from 20 sequential liver transplant recipients for at least 8 weeks following transplantation were tested by the PCR amplification procedure. Results were correlated with blood and urine cultures, histopathological findings from infected organs, and clinical manifestations. Six patients (30%) developed symptomatic CMV infection; in five (83%) of these patients, CMV DNA was detected prior to symptomatic CMV infection, and in one (17%) of these patients, CMV DNA was detected at the time of symptomatic CMV infection. CMV DNA was detected a mean of 13 days (range, 0 to 23 days) prior to the onset of symptomatic CMV infection. In addition, CMV DNA was detected in the sera of four of five patients with asymptomatic viremia and two patients with asymptomatic viruria. Lastly, the PCR was negative for sera from seven patients with no evidence of CMV infection. We found that PCR was able to detect the presence of CMV DNA in the sera of liver transplant recipients at a sensitivity of 92% and a specificity of 100% for CMV infection, while the sensitivity and specificity for symptomatic infection were 100 and 57%, respectively.

Base Sequence↗
PubMed1993

Solid organ transplantation: results and implications of acyclovir use in liver transplants.

CMV infection is a major cause of morbidity and mortality following liver transplantation (LT). A prospective study of 218 LT recipients showed that 55% of patients developed CMV infection during the 1st year post-transplantation. Symptomatic CMV infection developed in 25% of all patients, being a major cause of death (21% of all deaths). Of 62 episodes of documented organ invasion, liver was the major site (38 episodes), followed by lung (20), gastrointestinal (4), and retina (4). The main patient group at risk (according to CMV serology of the recipient [(R)/donor(D)]) was the R-/D+: 77% of patients developed CMV infection, all of them with symptoms. The lowest group at risk was the R-/D-: 13% of patients developed CMV infection, half of whom developed symptoms. Time-dependent multivariate statistical analysis of risk factors indicated that the R-/D+ group was the main risk factor for CMV infection (P < .02) and symptomatic infection (P < .0001). To decrease the incidence and severity of CMV infection following LT, a randomized study is ongoing to evaluate the efficacy of ganciclovir (5 mg/kg/IV/q 12 hours for the first 14 days post-LT) followed by acyclovir (800 mg/po/qid for 14 weeks) GCV + ACV (group I), versus acyclovir (same dose for 16 weeks, starting immediately post-LT) ACV (group II). These treatment groups are compared to matched historical controls (C). Preliminary analysis of 83 LT recipients indicates that in group I the median date for the first evidence of CMV infection is delayed (82 days) as compared to group II and C (41 and 33 days, respectively) (P = .004).(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗
PubMed1993

Risk factors for cytomegalovirus and severe bacterial infections following liver transplantation: a prospective multivariate time-dependent analysis.

Risk factors for cytomegalovirus and severe bacterial infections were studied prospectively by univariate, multivariate and time-dependent Cox model analysis in 79 consecutive liver transplant patients treated with selective bowel decontamination. Cytomegalovirus infection occurred in 39 patients (49%) and was symptomatic in 22 patients. Twenty-six patients (33%) developed at least one of 43 documented severe bacterial infections. In a multivariate analysis of risk factors for all cytomegalovirus infections, the cytomegalovirus seronegative recipient-cytomegalovirus seropositive donor group was the highest risk group (P < 0.001). Using the same analysis for risk factors for symptomatic cytomegalovirus infections, a prolonged prothrombin time (P < 0.005), a diagnosis of acute fulminant hepatitis as the underlying liver disease (P < 0.01) and a cytomegalovirus seronegative patient receiving a liver from a seropositive donor (P < 0.001) were significant. The treatment with OKT3 therapy (P < 0.008) and hepatic artery thrombosis (P < 0.02) were found to be significant risk factors in a time-dependent univariate analysis but were not independent risk factors when multivariate analysis was utilized. Significant risk factors for major bacterial infections (P < 0.03) using univariate analysis included a prolonged anesthesia, anhepatic and surgical times, as well as the transfusion of large amounts of fresh frozen plasma or autologous blood. In a multivariate analysis, only the transfusion of large amounts of fresh frozen plasma (P < 0.04) was a significant independent risk factor. Cytomegalovirus infection was a risk factor for the development of severe bacterial infections (P < 0.03) in a multivariate time-dependent analysis.

Adult↗
PubMed1993

Fungal infections in solid-organ transplantation.

Fungal infections following solid-organ transplantation remain a major cause of morbidity and death. Their incidence ranges from 5% among recipients of kidney transplants to as high as 40% among recipients of liver transplants. Species of Candida and Aspergillus account for more than 80% of fungal episodes. Moreover, more than 80% of fungal infections occur within the first 2 months after transplantation, with a resulting mortality of 30%-100%. The pathogenesis of infection and the risk factors involved depend on the type of transplant and the infecting microorganism. Cyclosporine has not significantly reduced the incidence or severity of fungal infections in this population. The value of surveillance cultures and fungal antigen detection in solid-organ transplant recipients remains to be determined. Amphotericin B is still a first-line drug, but its potential nephrotoxicity makes its use problematic, especially in renal transplant recipients. Fluconazole is a potential alternative for the treatment of infections due to Candida species and Cryptococcus neoformans. The role of antifungal compounds in the prophylaxis of fungal infection in recipients of solid-organ transplants needs to be established.

Heart Transplantation↗
PubMed1993

Antagonistic modulation of human cytomegalovirus replication by transforming growth factor beta and basic fibroblastic growth factor.

We studied the effect of two cytokines, basic fibroblastic growth factor (bFGF) and transforming growth factor beta (TGF-beta) on human cytomegalovirus (HCMV) replication in cultured human lung fibroblasts. We show that TGF-beta increases HCMV production, probably by a transcriptional mechanism, and that bFGF represses HCMV replication in a dose-dependent manner. These actions were antagonistic and the mechanisms involved were independent of the effects of these factors on cell DNA synthesis and proliferation.

Cells, Cultured↗
PubMed1993

Advances in the diagnosis, treatment, and prevention of cytomegalovirus infections after liver transplantation.

CMV is one of the most frequent viral infections after orthotopic liver transplantation. Thus, there should be a high index of clinical suspicion, particularly in liver transplant recipients who have risk factors for the development of CMV disease, including donor CMV seropositivity, the use of antilymphocyte preparations, and retransplantation. The availability of effective antiviral therapy to treat CMV disease has emphasized the importance of an aggressive approach to the early diagnosis and treatment of this viral infection. Ganciclovir has been a major advancement in the treatment of severe CMV disease and has had a major impact on reducing the incidence and severity of CMV disease and its complications in the liver transplant recipient. Furthermore, these antiviral agents are now being evaluated for their prophylactic potential. Indeed, a number of these agents or combinations of these agents have been shown to be effective in reducing the incidence and severity of CMV disease, particularly in the CMV-seropositive transplant recipient; however, the cost-effectiveness of such therapy and its overall impact on long-term graft and patient outcome remain poorly defined at this time. Further investigations will be needed to define the role and importance of prophylactic therapy for the prevention of CMV infection and disease in the liver transplant recipient.

Cytomegalovirus Infections↗