carlos Paya - Academia.edu (original) (raw)

Papers by carlos Paya

Journal of Virology, 1999

Human monocytes and macrophages are persistent reservoirs of human immunodeficiency virus (HIV) t... more Human monocytes and macrophages are persistent reservoirs of human immunodeficiency virus (HIV) type-1. Persistent HIV infection of these cells results in increased levels of NF-κB in the nucleus secondary to increased IκBα, IκBβ, and IκBɛ degradation, a mechanism postulated to regulate viral persistence. To characterize the molecular mechanisms regulating HIV-mediated degradation of IκB, we have sought to identify the regulatory domains of IκBα targeted by HIV infection. Using monocytic cells stably expressing different transdominant molecules of IκBα, we determined that persistent HIV infection of these cells targets the NH 2 but not the COOH terminus of IκBα. Further analysis demonstrated that phosphorylation at S 32 and S 36 is necessary for HIV-dependent IκBα degradation and NF-κB activation. Of the putative N-terminal IκBα kinases, we demonstrated that the Iκκ complex, but not p90 rsk , is activated by HIV infection and mediates HIV-dependent NF-κB activation. Analysis of vira...

Transplantation, 2007

Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like... more Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.

Transplantation, 2004

Background. Cytomegalovirus (CMV) Dϩ/RϪ solid-organ transplant (SOT) recipients carry increased r... more Background. Cytomegalovirus (CMV) Dϩ/RϪ solid-organ transplant (SOT) recipients carry increased risk of developing CMV disease; however, other risk factors in these patients have not been delineated. Methods. We examined 20 demographic and clinical variables for their association with the development of CMV disease, as defined by an independent endpoint committee (IEC) and also by the investigator (investigator treated [IT]), or CMV viremia within 12 months of transplant in Dϩ/RϪ transplant recipients who received prophylaxis with valganciclovir or oral ganciclovir for 100 days. Results. Recipients with low creatinine clearance (C cr ,Ͻ40 mL/min) at screening had a significantly increased hazard of developing IEC-defined CMV disease (hazards ratio [HR]ϭ4.28, confidence interval [CI] 1.69, 10.83). Females were twice as likely (HRϭ2.19, CI .21, 3.99) to develop IEC-defined CMV disease than males. These variables were associated with an increased risk of IEC-defined CMV disease in time-dependent models. Recipients with blood group A were also more likely to develop IEC-defined CMV disease than those with group O (HRϭ2.36 CI 1.24, 4.51) in the logistic regression model only. Prophylactic drug, organ type, recipient age, rejection episodes, and maintenance immunosuppression regimen were not associated with IEC-defined CMV disease. Female sex was the only variable associated with the development of CMV viremia (odds ratio [OR]ϭ1.65; CI 1.03, 2.65) and IT CMV disease (ORϭ1.78; CI 1.08, 2.93). Conclusions. Low C cr at screening and blood type A are risk factors for IEC-defined CMV disease, and female sex was a risk factor for IEC-and IT-defined CMV disease and viremia in high-risk SOT recipients. These variables should perhaps be considered when optimizing treatment.

Transplantation, 1998

Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft ... more Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft and patient survival among heart transplant recipients. We sought to explore the effect of CMV infection and disease on long-term survival in orthotopic liver transplant (OLT) recipients using a derivation and validation cohort. For derivation-validation modeling, we used data collected from two prospectively followed cohorts as the basis for multivariate analyses: 167 OLT recipients from the Boston Center for Liver Transplantation (the derivation set; median follow-up: 5.5 years, mortality: 40%) and an independent cohort of 294 OLT recipients from the Mayo Clinic (the validation set; median follow-up: 4.8 years, mortality: 27%). Underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis, number of units of red blood cells administered during transplantation, and donor CMV seropositivity were the pre- and intratransplant variables independently associated (P<0.01) with decreased long-term survival in the derivation cohort. For variables collected up to 1 year after transplantation, the need for retransplan. tation, CMV pneumonia, invasive fungal disease, and underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis were independently associated (P<0.01) with decreased long-term survival in the derivation cohort. The magnitude of the relationship of each pre-, intra-, and posttransplant factor with survival, as measured by the relative risk, did not significantly differ between the derivation and validation cohorts. The derivation model, incorporating pre-, intra-, and posttransplant factors, had receiver operating characteristic areas of 73% and 74% for 5-year mortality in the derivation and validation cohorts, respectively. Data from a derivation and an independent validation cohort demonstrate that CMV factors (reflected by either donor CMV seropositivity at transplantation, CMV pneumonia, or CMV disease within the first posttransplant year) are independently associated with decreased long-term survival in OLT recipients.

Surgical Clinics of North America, 1998

Since the inception of renal transplantation in the early 1960s, infectious diseases have been a ... more Since the inception of renal transplantation in the early 1960s, infectious diseases have been a constant yet evolving problem. The changing patterns of infectious disease complications in renal transplant recipients, primarily toward a reduction in the incidence and severity, can be attributed to multiple factors: improved surgical techniques, alterations and improvement in immunosuppressive regimens, institution of prophylactic antimicrobial agents, better diagnostic armamentarium, and the availability of more effective means of preventing and treating certain types of infection. This is reflected by the fact that during the first decades of the renal transplantation era, a serious infectious complication developed in up to 70% of patients following transplant, resulting in fatal outcomes in as many as 11% to 40% of cases.', 11, 22, 26, 35, 36, 38, 43, 49 Recent studies have described an incidence of 15% to 44%, with mortality rate due to infections of less than 5?'03, 4, 14, 17, 18, 34, 39, 43, 45 (Table 1). Nevertheless, the challenge remains because infections continue to be an extremely important cause of post-transplant morbidity and a leading cause of death of renal allograft recipients at all points in the postsurgical course.22, %, 38, 42 Moreover, the introduction of more potent immunosuppressive agents may result in the resurgence of certain infectious complications. Hence, the prevention and effective treatment of infectious complications remain major concerns of the transplant clinicians. The risk of infection in the renal transplant recipient is determined primarily by two factors: epidemiologic exposures to the infective agents and the net state of immunosuppression prior to transplantation (Table From the

Oncogene, 2001

RelA and RelB are two members of the NF-kB family that dier structurally and functionally. While ... more RelA and RelB are two members of the NF-kB family that dier structurally and functionally. While RelA is regulated through its cytosolic localization by inhibitor proteins or IkB and not through transcriptional mechanisms, the regulation of RelB is poorly understood. In this study we demonstrate that stimuli (TNF or LPS) lead within minutes to the nuclear translocation of RelA, but require hours to result in the nuclear translocation of RelB. The delayed nuclear translocation of RelB correlates with increases in its protein synthesis which are secondary to increases in RelB gene transcription. RelA is alone sucient to induce RelB gene transcription and to mediate the stimuli-driven increase in RelB transcription. Cloning and characterization of the RelB 5' untranslated gene region indicates that RelB transcription is dependent on a TATA-less promoter containing two NF-kB binding sites. One of the NF-kB sites is primarily involved in the binding of p50 while the other one in the binding and transactivation by RelA and also RelB. Lastly, it is observed that p21, a protein involved in cell cycle control and oncogenesis known to be regulated by NF-kB, is upregulated at the transcriptional level by RelB. Thus, RelB is regulated at least at the level of transcription in a RelA and RelB dependent manner and may exert an important role in p21 regulation. Oncogene (2001) 20, 7722 ± 7733.

Mayo Clinic Proceedings, 1989

ABSTRACT

Liver Transplantation and Surgery, 1996

The Journal of Infectious Diseases, 2004

We investigated the emergence of cytomegalovirus (CMV) ganciclovir-resistance mutations in 301 hi... more We investigated the emergence of cytomegalovirus (CMV) ganciclovir-resistance mutations in 301 high-risk solid-organ transplant (SOT) recipients after oral prophylaxis, for 100 days, with either valganciclovir or ganciclovir. For patients treated with ganciclovir, the incidence of CMV UL97 mutations was 1.9% (2/103) at the end of prophylaxis and 6.1% (2/33) for patients with suspected CMV disease up to 1 year after transplantation. No resistance mutations were detected in samples from valganciclovir-treated patients. Dual polymerase (UL54) and UL97 resistance mutations were not seen. Valganciclovir was associated with negligible risk of resistance and thus constitutes a useful alternative to ganciclovir prophylaxis for CMV in high-risk SOT recipients. Ganciclovir is currently the drug of choice for the prevention and treatment of cytomegalovirus (CMV) disease, and its use

The Journal of Infectious Diseases, 2002

The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent in... more The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent infection and disease in solid-organ transplant patients has not been evaluated by placebo-controlled trials. We carried out such a study in 69 patients who had received liver transplants and had positive results of CMV polymerase chain reaction within 8 weeks after transplantation but did not have concomitant CMV infection or disease. These patients were randomly assigned to receive placebo or oral ganciclovir for 8 weeks. CMV infection developed in 21% and disease developed in 12% of placebo recipients (P ¼ .022), compared with 3% and 0%, respectively, among ganciclovir recipients (P ¼ .003). Similarly, in the placebo arm, 55% and 36% of CMV-negative patients who received organs from CMV-positive donors developed CMV infection or disease, respectively (P ¼ .02), compared with 11% and 0% of such patients in the ganciclovir arm (P , .01). Oral ganciclovir administered on CMV detection by PCR prevents CMV infection or disease after liver transplantation.

Journal of Allergy and Clinical Immunology, 2002

Hepatology, 1990

Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen... more Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen or a polyclonal antibody, in situ DNA hybridization and inoculation of cell cultures for the detection of cytomegalovirus from liver biopsy specimens were studied in 20 liver transplant patients with cytomegalovirus hepatitis, as defined by histological criteria. A total of 108 liver biopsy specimens from 20 patients with a diagnosis of cytomegalovirus hepatitis (obtained per protocol at 7, 21, 90, and 180 days or whenever liver dysfunction occurred), which had previously been examined histologically and in cell culture, were again studied by recutting the liver tissue for histological examination, DNA hybridization and immunostaining with monoclonal or polyclonal antibodies to cytomegalovirus. In 5 of 20 patients, the diagnosis of cytomegalovirus hepatitis could have been made earlier (mean = 9.6 days) by immunostaining with a monoclonal antibody. Of 47 biopsy specimens with cytomegalovirus inclusion bodies, the sensitivity and specificity of the diagnostic procedures were immunostaining with monoclonal antibody (84% and 90%) and polyclonal antibody (72% and 97%), in situ DNA hybridization (72% and 100%) and cell culture detection (52% and 95%), respectively. Immunostaining with a monoclonal antibody against an early CMV antigen frequently detected cytomegalovirus infection in the liver allograft earlier than identification of typical histological inclusion bodies. DNA in situ hybridization was less sensitive than other techniques but highly specific; cytomegalovirus cell culture lacked sensitivity compared with the other procedures.

Clinical Pharmacokinetics, 2005

prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negat... more prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R-]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R-(intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed. Methods: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene  , 1000mg three times daily) and from valganciclovir (900mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed. Results: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area

American Journal of Transplantation, 2005

Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R- solid organ transplant... more Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R- solid organ transplant (SOT) patients who receive antiviral prophylaxis. We assessed the clinical utility of CMV IgG and IgM serology testing for predicting late-onset CMV disease. We evaluated 352 D+/R- transplant recipients who participated in a trial comparing 100 days of ganciclovir versus valganciclovir prophylaxis. CMV serology was assessed on day 28, 56, 100, and 6 and 12 months post-transplant. IgG seroconversion occurred in 26.9% of patients by day 100, and in 63.4% and 75.3% by 6 and 12 months, respectively. IgM seroconversion occurred in 8.3%, 41.8% and 54.9% by day 100, month 6 and month 12, respectively. Seroconversion by day 100 (end of prophylaxis) was not predictive of subsequent CMV disease (CMV disease 13.3% if seropositive vs. 17.8% if seronegative; p = NS). However, at 6 months post-transplant, IgG serostatus was predictive of subsequent CMV disease between month 6 and 12 (CMV disease 1.3% if seropositive vs. 10.0% if seronegative; p = 0.002). In D+/R- patients, CMV serology testing is for the most part not clinically useful for predicting subsequent disease. However, seroconversion by 6 months may be useful for identifying patients at risk of late-onset CMV disease.

American Journal of Transplantation, 2004

We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventin... more We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R-patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigatortreated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p = 0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, oncedaily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.

International Immunology, 1995

Previous studies have demonstrated that IL-1 receptor (IL-1R)- and TCR-initiated signals can inte... more Previous studies have demonstrated that IL-1 receptor (IL-1R)- and TCR-initiated signals can interact synergistically to increase the rate of transcription of several lymphokine and lymphokine receptor genes during the competence phase of the activation program in T helper lymphocytes. In this report we describe how signals initiated through the type I IL-1R interact with signals from the antigen receptor to synergistically augment the transactivating properties of NF-kappa B. The synergistic antigen receptor initiated signals are mediated through protein kinase C because they can be mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, but not with calcium ionophores; and are staurosporine sensitive but cyclosporine resistant. Gel shift analyses demonstrate that NF-kappa B nuclear translocation is stimulated primarily by IL-1 rather than by antigen receptor signals. Western blot and phosphorylation analyses demonstrate that the synergistic effect on NF-kappa B functional activity is independent of I kappa B alpha (MAD3)-NF-kappa B dissociation in the cytosol and is not associated with I kappa B nuclear translocation. The IL-1-induced NF-kappa B DNA nuclear localization is transient and can be prolonged either by an antigen receptor-initiated signal or by inhibiting protein synthesis. These results suggest that IL-1 induces both NF-kappa B nuclear translocation and the synthesis of a protein(s) responsible for terminating NF-kappa B-DNA interaction in the nucleus. Antigen receptor signals prolong NF-kappa B-DNA interaction, probably by functionally antagonizing the IL-1-induced synthesis of a protein(s) responsible for the transient NF-kappa B-DNA interaction and consequently synergistically enhance IL-1-induced NF-kappa B-dependent gene transcription.

Journal of Virology, 1999

Human monocytes and macrophages are persistent reservoirs of human immunodeficiency virus (HIV) t... more Human monocytes and macrophages are persistent reservoirs of human immunodeficiency virus (HIV) type-1. Persistent HIV infection of these cells results in increased levels of NF-κB in the nucleus secondary to increased IκBα, IκBβ, and IκBɛ degradation, a mechanism postulated to regulate viral persistence. To characterize the molecular mechanisms regulating HIV-mediated degradation of IκB, we have sought to identify the regulatory domains of IκBα targeted by HIV infection. Using monocytic cells stably expressing different transdominant molecules of IκBα, we determined that persistent HIV infection of these cells targets the NH 2 but not the COOH terminus of IκBα. Further analysis demonstrated that phosphorylation at S 32 and S 36 is necessary for HIV-dependent IκBα degradation and NF-κB activation. Of the putative N-terminal IκBα kinases, we demonstrated that the Iκκ complex, but not p90 rsk , is activated by HIV infection and mediates HIV-dependent NF-κB activation. Analysis of vira...

Transplantation, 2007

Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like... more Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.

Transplantation, 2004

Background. Cytomegalovirus (CMV) Dϩ/RϪ solid-organ transplant (SOT) recipients carry increased r... more Background. Cytomegalovirus (CMV) Dϩ/RϪ solid-organ transplant (SOT) recipients carry increased risk of developing CMV disease; however, other risk factors in these patients have not been delineated. Methods. We examined 20 demographic and clinical variables for their association with the development of CMV disease, as defined by an independent endpoint committee (IEC) and also by the investigator (investigator treated [IT]), or CMV viremia within 12 months of transplant in Dϩ/RϪ transplant recipients who received prophylaxis with valganciclovir or oral ganciclovir for 100 days. Results. Recipients with low creatinine clearance (C cr ,Ͻ40 mL/min) at screening had a significantly increased hazard of developing IEC-defined CMV disease (hazards ratio [HR]ϭ4.28, confidence interval [CI] 1.69, 10.83). Females were twice as likely (HRϭ2.19, CI .21, 3.99) to develop IEC-defined CMV disease than males. These variables were associated with an increased risk of IEC-defined CMV disease in time-dependent models. Recipients with blood group A were also more likely to develop IEC-defined CMV disease than those with group O (HRϭ2.36 CI 1.24, 4.51) in the logistic regression model only. Prophylactic drug, organ type, recipient age, rejection episodes, and maintenance immunosuppression regimen were not associated with IEC-defined CMV disease. Female sex was the only variable associated with the development of CMV viremia (odds ratio [OR]ϭ1.65; CI 1.03, 2.65) and IT CMV disease (ORϭ1.78; CI 1.08, 2.93). Conclusions. Low C cr at screening and blood type A are risk factors for IEC-defined CMV disease, and female sex was a risk factor for IEC-and IT-defined CMV disease and viremia in high-risk SOT recipients. These variables should perhaps be considered when optimizing treatment.

Transplantation, 1998

Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft ... more Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft and patient survival among heart transplant recipients. We sought to explore the effect of CMV infection and disease on long-term survival in orthotopic liver transplant (OLT) recipients using a derivation and validation cohort. For derivation-validation modeling, we used data collected from two prospectively followed cohorts as the basis for multivariate analyses: 167 OLT recipients from the Boston Center for Liver Transplantation (the derivation set; median follow-up: 5.5 years, mortality: 40%) and an independent cohort of 294 OLT recipients from the Mayo Clinic (the validation set; median follow-up: 4.8 years, mortality: 27%). Underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis, number of units of red blood cells administered during transplantation, and donor CMV seropositivity were the pre- and intratransplant variables independently associated (P<0.01) with decreased long-term survival in the derivation cohort. For variables collected up to 1 year after transplantation, the need for retransplan. tation, CMV pneumonia, invasive fungal disease, and underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis were independently associated (P<0.01) with decreased long-term survival in the derivation cohort. The magnitude of the relationship of each pre-, intra-, and posttransplant factor with survival, as measured by the relative risk, did not significantly differ between the derivation and validation cohorts. The derivation model, incorporating pre-, intra-, and posttransplant factors, had receiver operating characteristic areas of 73% and 74% for 5-year mortality in the derivation and validation cohorts, respectively. Data from a derivation and an independent validation cohort demonstrate that CMV factors (reflected by either donor CMV seropositivity at transplantation, CMV pneumonia, or CMV disease within the first posttransplant year) are independently associated with decreased long-term survival in OLT recipients.

Surgical Clinics of North America, 1998

Since the inception of renal transplantation in the early 1960s, infectious diseases have been a ... more Since the inception of renal transplantation in the early 1960s, infectious diseases have been a constant yet evolving problem. The changing patterns of infectious disease complications in renal transplant recipients, primarily toward a reduction in the incidence and severity, can be attributed to multiple factors: improved surgical techniques, alterations and improvement in immunosuppressive regimens, institution of prophylactic antimicrobial agents, better diagnostic armamentarium, and the availability of more effective means of preventing and treating certain types of infection. This is reflected by the fact that during the first decades of the renal transplantation era, a serious infectious complication developed in up to 70% of patients following transplant, resulting in fatal outcomes in as many as 11% to 40% of cases.', 11, 22, 26, 35, 36, 38, 43, 49 Recent studies have described an incidence of 15% to 44%, with mortality rate due to infections of less than 5?'03, 4, 14, 17, 18, 34, 39, 43, 45 (Table 1). Nevertheless, the challenge remains because infections continue to be an extremely important cause of post-transplant morbidity and a leading cause of death of renal allograft recipients at all points in the postsurgical course.22, %, 38, 42 Moreover, the introduction of more potent immunosuppressive agents may result in the resurgence of certain infectious complications. Hence, the prevention and effective treatment of infectious complications remain major concerns of the transplant clinicians. The risk of infection in the renal transplant recipient is determined primarily by two factors: epidemiologic exposures to the infective agents and the net state of immunosuppression prior to transplantation (Table From the

Oncogene, 2001

RelA and RelB are two members of the NF-kB family that dier structurally and functionally. While ... more RelA and RelB are two members of the NF-kB family that dier structurally and functionally. While RelA is regulated through its cytosolic localization by inhibitor proteins or IkB and not through transcriptional mechanisms, the regulation of RelB is poorly understood. In this study we demonstrate that stimuli (TNF or LPS) lead within minutes to the nuclear translocation of RelA, but require hours to result in the nuclear translocation of RelB. The delayed nuclear translocation of RelB correlates with increases in its protein synthesis which are secondary to increases in RelB gene transcription. RelA is alone sucient to induce RelB gene transcription and to mediate the stimuli-driven increase in RelB transcription. Cloning and characterization of the RelB 5' untranslated gene region indicates that RelB transcription is dependent on a TATA-less promoter containing two NF-kB binding sites. One of the NF-kB sites is primarily involved in the binding of p50 while the other one in the binding and transactivation by RelA and also RelB. Lastly, it is observed that p21, a protein involved in cell cycle control and oncogenesis known to be regulated by NF-kB, is upregulated at the transcriptional level by RelB. Thus, RelB is regulated at least at the level of transcription in a RelA and RelB dependent manner and may exert an important role in p21 regulation. Oncogene (2001) 20, 7722 ± 7733.

Mayo Clinic Proceedings, 1989

ABSTRACT

Liver Transplantation and Surgery, 1996

The Journal of Infectious Diseases, 2004

We investigated the emergence of cytomegalovirus (CMV) ganciclovir-resistance mutations in 301 hi... more We investigated the emergence of cytomegalovirus (CMV) ganciclovir-resistance mutations in 301 high-risk solid-organ transplant (SOT) recipients after oral prophylaxis, for 100 days, with either valganciclovir or ganciclovir. For patients treated with ganciclovir, the incidence of CMV UL97 mutations was 1.9% (2/103) at the end of prophylaxis and 6.1% (2/33) for patients with suspected CMV disease up to 1 year after transplantation. No resistance mutations were detected in samples from valganciclovir-treated patients. Dual polymerase (UL54) and UL97 resistance mutations were not seen. Valganciclovir was associated with negligible risk of resistance and thus constitutes a useful alternative to ganciclovir prophylaxis for CMV in high-risk SOT recipients. Ganciclovir is currently the drug of choice for the prevention and treatment of cytomegalovirus (CMV) disease, and its use

The Journal of Infectious Diseases, 2002

The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent in... more The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent infection and disease in solid-organ transplant patients has not been evaluated by placebo-controlled trials. We carried out such a study in 69 patients who had received liver transplants and had positive results of CMV polymerase chain reaction within 8 weeks after transplantation but did not have concomitant CMV infection or disease. These patients were randomly assigned to receive placebo or oral ganciclovir for 8 weeks. CMV infection developed in 21% and disease developed in 12% of placebo recipients (P ¼ .022), compared with 3% and 0%, respectively, among ganciclovir recipients (P ¼ .003). Similarly, in the placebo arm, 55% and 36% of CMV-negative patients who received organs from CMV-positive donors developed CMV infection or disease, respectively (P ¼ .02), compared with 11% and 0% of such patients in the ganciclovir arm (P , .01). Oral ganciclovir administered on CMV detection by PCR prevents CMV infection or disease after liver transplantation.

Journal of Allergy and Clinical Immunology, 2002

Hepatology, 1990

Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen... more Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen or a polyclonal antibody, in situ DNA hybridization and inoculation of cell cultures for the detection of cytomegalovirus from liver biopsy specimens were studied in 20 liver transplant patients with cytomegalovirus hepatitis, as defined by histological criteria. A total of 108 liver biopsy specimens from 20 patients with a diagnosis of cytomegalovirus hepatitis (obtained per protocol at 7, 21, 90, and 180 days or whenever liver dysfunction occurred), which had previously been examined histologically and in cell culture, were again studied by recutting the liver tissue for histological examination, DNA hybridization and immunostaining with monoclonal or polyclonal antibodies to cytomegalovirus. In 5 of 20 patients, the diagnosis of cytomegalovirus hepatitis could have been made earlier (mean = 9.6 days) by immunostaining with a monoclonal antibody. Of 47 biopsy specimens with cytomegalovirus inclusion bodies, the sensitivity and specificity of the diagnostic procedures were immunostaining with monoclonal antibody (84% and 90%) and polyclonal antibody (72% and 97%), in situ DNA hybridization (72% and 100%) and cell culture detection (52% and 95%), respectively. Immunostaining with a monoclonal antibody against an early CMV antigen frequently detected cytomegalovirus infection in the liver allograft earlier than identification of typical histological inclusion bodies. DNA in situ hybridization was less sensitive than other techniques but highly specific; cytomegalovirus cell culture lacked sensitivity compared with the other procedures.

Clinical Pharmacokinetics, 2005

prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negat... more prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R-]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R-(intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed. Methods: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene  , 1000mg three times daily) and from valganciclovir (900mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed. Results: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area

American Journal of Transplantation, 2005

Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R- solid organ transplant... more Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R- solid organ transplant (SOT) patients who receive antiviral prophylaxis. We assessed the clinical utility of CMV IgG and IgM serology testing for predicting late-onset CMV disease. We evaluated 352 D+/R- transplant recipients who participated in a trial comparing 100 days of ganciclovir versus valganciclovir prophylaxis. CMV serology was assessed on day 28, 56, 100, and 6 and 12 months post-transplant. IgG seroconversion occurred in 26.9% of patients by day 100, and in 63.4% and 75.3% by 6 and 12 months, respectively. IgM seroconversion occurred in 8.3%, 41.8% and 54.9% by day 100, month 6 and month 12, respectively. Seroconversion by day 100 (end of prophylaxis) was not predictive of subsequent CMV disease (CMV disease 13.3% if seropositive vs. 17.8% if seronegative; p = NS). However, at 6 months post-transplant, IgG serostatus was predictive of subsequent CMV disease between month 6 and 12 (CMV disease 1.3% if seropositive vs. 10.0% if seronegative; p = 0.002). In D+/R- patients, CMV serology testing is for the most part not clinically useful for predicting subsequent disease. However, seroconversion by 6 months may be useful for identifying patients at risk of late-onset CMV disease.

American Journal of Transplantation, 2004

We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventin... more We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R-patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigatortreated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p = 0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, oncedaily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.

International Immunology, 1995

Previous studies have demonstrated that IL-1 receptor (IL-1R)- and TCR-initiated signals can inte... more Previous studies have demonstrated that IL-1 receptor (IL-1R)- and TCR-initiated signals can interact synergistically to increase the rate of transcription of several lymphokine and lymphokine receptor genes during the competence phase of the activation program in T helper lymphocytes. In this report we describe how signals initiated through the type I IL-1R interact with signals from the antigen receptor to synergistically augment the transactivating properties of NF-kappa B. The synergistic antigen receptor initiated signals are mediated through protein kinase C because they can be mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, but not with calcium ionophores; and are staurosporine sensitive but cyclosporine resistant. Gel shift analyses demonstrate that NF-kappa B nuclear translocation is stimulated primarily by IL-1 rather than by antigen receptor signals. Western blot and phosphorylation analyses demonstrate that the synergistic effect on NF-kappa B functional activity is independent of I kappa B alpha (MAD3)-NF-kappa B dissociation in the cytosol and is not associated with I kappa B nuclear translocation. The IL-1-induced NF-kappa B DNA nuclear localization is transient and can be prolonged either by an antigen receptor-initiated signal or by inhibiting protein synthesis. These results suggest that IL-1 induces both NF-kappa B nuclear translocation and the synthesis of a protein(s) responsible for terminating NF-kappa B-DNA interaction in the nucleus. Antigen receptor signals prolong NF-kappa B-DNA interaction, probably by functionally antagonizing the IL-1-induced synthesis of a protein(s) responsible for the transient NF-kappa B-DNA interaction and consequently synergistically enhance IL-1-induced NF-kappa B-dependent gene transcription.