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A D Badley

Publications and source records attributed to A D Badley.

At least 37 records · Page 2Linked to original sources
PubMed1999

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection.

T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P<0.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBL's from HIV negative patients, and apoptosis sensitive PBL's from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

Adolescent↗
PubMed1998

In vivo analysis of Fas/FasL interactions in HIV-infected patients.

Recent insights into the pharmacological control of HIV replication and the molecular mechanisms of peripheral T cells homeostasis allowed us to investigate in vivo the mechanisms mediating T cell depletion in HIV-infected patients. Before the initiation of highly active antiretroviral therapy (HAART), a high degree of lymphoid tissue apoptosis is present, which is reduced upon HAART initiation (P < 0.001) and directly correlates with reduction of viral load and increases of peripheral T lymphocytes (P < 0.01). Because Fas/FasL interactions play a key role in peripheral T lymphocyte homeostasis, we investigated the susceptibility to Fas-mediated apoptosis in peripheral T lymphocytes and of FasL expression in lymphoid tissue before and during HAART. High levels of Fas-susceptibility found in peripheral CD4 T lymphocytes before HAART were significantly reduced after HAART, coinciding with decreases in viral load (P = 0.018) and increases in peripheral CD4 T lymphocyte counts (P < 0.01). However, the increased FasL expression in the lymphoid tissue of HIV-infected individuals was not reduced after HAART. These results demonstrate that lymphoid tissue apoptosis directly correlates with viral load and peripheral T lymphocyte numbers, and suggest that HIV-induced susceptibility to Fas-dependent apoptosis may play a key role in the regulation of T cell homeostasis in HIV-infected individuals.

Anti-HIV Agents↗
PubMed1998

The expression of Fas Ligand by macrophages and its upregulation by human immunodeficiency virus infection.

Fas/Fas Ligand (FasL) interactions play a significant role in peripheral T lymphocyte homeostasis and in certain pathological states characterized by T cell depletion. In this study, we demonstrate that antigen-presenting cells such as monocyte-derived human macrophages (MDM) but not monocyte-derived dendritic cells express basal levels of FasL. HIV infection of MDM increases FasL protein expression independent of posttranslational mechanisms, thus highlighting the virus-induced transcriptional upregulation of FasL. The in vitro relevance of these observations is confirmed in human lymphoid tissue. FasL protein expression is constitutive and restricted to tissue macrophages and not dendritic cells. Moreover, a significant increase in macrophage-associated FasL is observed in lymphoid tissue from HIV (+) individuals (P < 0.001), which is further supported by increased levels of FasL mRNA using in situ hybridization. The degree of FasL protein expression in vivo correlates with the degree of tissue apoptosis (r = 0.761, P < 0. 001), which is significantly increased in tissue from HIV-infected patients (P < 0.001). These results identify human tissue macrophages as a relevant source for FasL expression in vitro and in vivo and highlight the potential role of FasL expression in the immunopathogenesis of HIV infection.

Apoptosis↗
PubMed1998

Transcriptional regulation of the human FasL promoter-enhancer region.

The human FasL enhancer region was cloned and functionally characterized in transformed and primary T cells. Within the 2.3 kilobase pairs of the FasL untranslated region, the distal 3' 300-base pair portion contains a single transcription initiation site and confers basal and inducible transcriptional activity. Stimuli that increase [Ca2+]i such as CD3 cross-linking or ionomycin, but not activation of protein kinase C, were found to induce FasL enhancer transcription in a cyclosporin-sensitive manner. Moreover, calcineurin and NFAT, but not AP1, were identified as necessary and sufficient effectors in driving FasL transcription through an NFAT cis-acting motif (GGAAA). Additional modes of T cell activation such as CD4 cross-linking were also found to induce NFAT binding to the FasL enhancer region and to functionally transactivate its transcription. These results indicate that the induction of FasL gene transcription in T cells after CD3 or CD4 activation is selectively mediated by calcineurin and NFAT.

Base Sequence↗
PubMed1998

Porphyria cutanea tarda and human immunodeficiency virus: two cases associated with hepatitis C.

Hepatitis C virus (HCV) was recently recognized as a probable etiologic factor for porphyria cutanea tarda (PCT). A review of the literature revealed 40 cases of PCT associated with the human immunodeficiency virus (HIV). In most of these cases, hepatitis C status was unknown. We describe two patients with PCT who were coinfected with HIV and HCV and discuss the interaction of these two viruses. A diagnosis of PCT, especially in a young patient, should prompt investigation for underlying HIV and HCV infection. Porphyrin studies should be performed in any patient with HIV and photosensitivity. Clinicians should be aware of the infectious risk associated with the vesicles and erosions in these patients.

Adult↗
PubMed1997

Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver Transplantation Database.

BACKGROUND: The optimal prophylactic regimen to prevent cytomegalovirus (CMV) infection and disease in orthotopic liver-transplant patients remains to be established. We tested whether a combination of intravenous ganciclovir (GCV) followed by high dosages of oral acyclovir (ACV) for 4 months provided a higher degree of protection from CMV than oral ACV alone. METHODS: One hundred sixty-seven liver-transplant recipients were randomized to receive 120 days of antiviral treatment starting at the time of transplantation consisting of either ACV 800 mg orally four times daily (n=84) or 14 days of GCV 5 mg/kg intravenously every 12 hr followed by oral ACV 800 mg four times daily (n=83). Prospective laboratory and clinical surveillance was performed to determine primary endpoints (onset of CMV infection and CMV disease) and secondary endpoints (rates of fungal and bacterial infection, allograft rejection, and survival after transplantation). One-year event rates are presented as cumulative percentages. RESULTS: During the first year after transplantation, CMV infection developed in 57% of patients treated with ACV and in 37% of patients treated with GCV + ACV (P=0.001). CMV disease developed in 23% of patients treated with ACV and in 11% of patients treated with GCV + ACV (P=0.03). In seronegative recipients of allografts from CMV-seropositive donors (D+/R-), CMV disease developed in 58% of patients treated with ACV and in 25% of patients treated with GCV + ACV (P=0.04). In the D+/R- group, 54% of patients treated with ACV and 17% of patients treated with GCV + ACV developed infection with Candida albicans (P=0.05). CONCLUSIONS: Prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous GCV followed by high-dosage oral ACV is more effective than high-dosage oral ACV alone at reducing CMV infection and disease, even for patients in the D+/R- CMV serological group.

Acyclovir↗
PubMed1997

Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.

Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

Antibodies, Monoclonal↗
PubMed1997

Apoptosis in AIDS.

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Acquired Immunodeficiency Syndrome↗
PubMed1997

Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease.

Human herpesvirus 6 (HHV-6) infection is common after transplantation; HHV-6 is known to interact with other viruses and induce immunosuppression. Whether HHV-6 plays a role in the occurrence of cytomegalovirus (CMV) infection after transplantation was investigated. In a cohort of 247 liver transplant recipients, HHV-6 seroconversion was identified as a significant risk factor for development of symptomatic CMV infection (P < .001), including CMV organ involvement (P < .001), even in the presence of the other significant risk factors: D+/R- CMV serologic status (P < .001) or use of OKT3 after transplantation (P = .002). Subgroup analysis indicated that HHV-6 seroconversion was significantly associated with symptomatic CMV infection in the D+/R+ but not in the D+/R- CMV serologic group (P < .001 and P = .11, respectively). These results indicate that HHV-6 seroconversion is a marker for CMV disease after transplantation and suggest that additional studies using more sensitive diagnostic techniques are warranted to determine the relationship between HHV-6 and CMV infection after transplantation.

Adult↗
PubMed1997

Infective endocarditis caused by HACEK microorganisms.

The HACEK group of fastidious gram-negative organisms is a recognized but unusual cause of infective endocarditis, responsible for approximately 3% of cases. We report our experience with 45 cases of endocarditis caused by HACEK organisms. In Olmsted County, Minnesota, the incidence of HACEK endocarditis was 0.14 per 100,000 person-years. In patients with native valves, 33 cases occurred, and in patients with prosthetic valves, 12 cases occurred. The most common presenting symptoms were fever, splenomegaly, new or changing murmur, and microvascular phenomena. Symptoms were present in the majority of patients anywhere from two weeks to six months prior to diagnosis. Blood cultures became positive in a mean 3.375 days, and therapy with a beta-lactam alone or as part of a combination was given for anywhere between three and six weeks. Within the first month of diagnosis, surgery was performed for 13 regurgitant valves in 11 patients (24%). Echocardiography was an insensitive predictor of subsequent major arterial embolization (odds ratio, 1.33; 95% confidence interval, 0.31-5.67). The overall survival in our cohort of patients was 87%. These results confirm previous reports that HACEK endocarditis portends a favorable prognosis.

Adult↗
PubMed1996

Risk factors of invasive Candida and non-Candida fungal infections after liver transplantation.

Fungal infections are associated with a high mortality rate after liver transplantation. To describe risk factors for fungal infections, 405 consecutive liver transplant recipients were analyzed. Forty-five patients (11%) developed invasive fungal infection. Median posttransplantation time to the first episode was 60 days. Pathogens were Candida species (spp) (n=24, 53%), Cryptococcus neoformans (n=10, 22%), Aspergillus spp (n=6, 13%), Rhizopus spp (n=l), and others (n=4). Presentations of infection included disseminated (n=9), intra-abdominal (n=9), esophageal (n=9), lung (n=8), blood (n=6), and central nervous system infections (n=3), and sinusitis with esophagitis (n=1). Eighteen patients (40%) with invasive fungal infection died, and 13 (72%) of these deaths were attributable to fungi. Mortality in the nonfungal infection group was 12%. Univariate analysis identified separate risk factors for Candida (intra-abdominal bleeding), Aspergillus (fulminant hepatitis), and cryptococcal (symptomatic cytomegalovirus infection) infections. In both univariate and multivariate analyses, a high intratransplant transfusion requirement and posttransplant bacterial infection were identified as significant risk factors for all types of fungal infection. The risk factor analysis reported here suggests that different pathogenic processes lead to Candida and non-Candida infection in liver transplant recipients. Their identification should prompt specific prophylactic measures to reduce morbidity and mortality in this population.

Analysis of Variance↗
PubMed1996

Relevance and risk factors of enterococcal bacteremia following liver transplantation.

To analyze the clinical characteristics of and identify specific risk factors for enterococcal bacteremia following liver transplantation, we performed a study in 405 consecutive liver transplantation recipients prophylaxed with a selective bowel decontamination regimen. Seventy enterococcal bacteremias in 52 patients were identified. Enterococcus faecalis (50) outnumbered Enterococcus faecium isolates (18), and 49% of enterococcal bacteremias were polymicrobial. Biliary tree complications were present in 34% of enterococcal bacteremias. Of the 15 deaths (29%) among the patients with enterococcal bacteremia, 4 were directly associated with enterococcal bacteremia. In a multivariate analysis, Roux-en-Y choledochojejunostomy (P=0.005), a cytomegalovirus-seropositive donor (P=0.013), prolonged transplantation time (P=0.02), and biliary stricturing (P=0.016) were identified as significant risk factors. Other risk factors identified in a univariate analysis included primary sclerosing cholangitis (P=0.009) and symptomatic cytomegalovirus infection (P=0.008). Enterococcal bacteremia is a frequent infectious complication in liver transplantation recipients receiving selective bowel decontamination. Its association with cytomegalovirus and biliary tree abnormalities suggest specific areas for prophylactic intervention.

Anastomosis, Roux-en-Y↗
PubMed1996

Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disorder (PTLD) develops in 3% to 10% of solid organ transplant recipients with a resultant mortality of up to 70%. Unfortunately, there is no current marker which identifies patients who will develop this disease. We therefore conducted a risk factor analysis of variables that might predict the development of PTLD. Specifically, since EBV may cause both PTLD and the development of monoclonal proteins (M protein), we sought to determine if the development of an M protein preceded and therefore might serve as a predictive marker of subsequent PTLD. Before and after liver transplantation, 201 patients were evaluated for the presence of urine and serum M proteins. Patients were followed to monitor the development of PTLD for a mean of 1,733 days. PTLD developed in seven patients (3.5%), three (43%) of whom died from disseminated PTLD. PTLD was classified as polymorphous in six patients and monomorphous in one patient. Fifty-seven patients (28%) developed an M protein after transplantation: five of seven patients (71%) with PTLD and 52/194 (27%) of patients without PTLD. Multivariate risk factor analysis for the development of an M protein after transplantation identified cytomegalovirus (CMV) donor seropositivity (P = 0.0002) and postoperative symptomatic CMV infection (P = 0.019) as risk factors. Whereas EBV serostatus of either the donor or recipient was not found to be a risk factor for the occurrence of either an M protein or PTLD, the development of a serum immunoglobulin M (IgM) M protein (P = 0.04) and of any urine M protein (P = 0.01) was identified by univariate analysis as being associated with the development of PTLD. Further studies are needed to determine the predictive value of M proteins as a marker for PTLD. Until such time, the development of serum or urine M protein should heighten the suspicion of developing PTLD.

Adolescent↗
PubMed1996

Prognostic significance and risk factors of untreated cytomegalovirus viremia in liver transplant recipients.

To study whether cytomegalovirus (CMV) viremia is a reliable marker of impending CMV disease and thus a guide for preemptive antiviral therapy, 126 consecutive liver transplant recipients were followed by routine CMV blood cultures in the absence of antiviral prophylaxis or treatment for viremia. Seventy-three patients (58%) developed CMV infections, and 36 (29%) had more than one infection episode: 29 patients (23%) had organ involvement and 45 (36%) had viremia. Within a same episode, CMV viremia was 90% sensitive and 80% specific for predicting concurrent organ involvement but preceded organ involvement in only 9 (31%) of 29 patients. In a separate analysis, untreated isolated CMV viremia in the first CMV infection episode was followed by organ involvement in a subsequent episode in 9 (33%) of 28 patients, mainly in the donor-positive, recipient-negative (D+/R-) population. The results indicate that CMV viremia is not an ideal marker to guide preemptive antiviral treatment in liver transplant recipients but is a good marker in D+/R- patients.

Adult↗
PubMed1996

Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes.

Apoptosis has been proposed to mediate CD4+ T-cell depletion in human immunodeficiency virus (HIV)-infected individuals. Interaction of Fas ligand (FasL) with Fas (CD95) results in lymphocyte apoptosis, and increased susceptibility to Fas-mediated apoptosis has been demonstrated in lymphocytes from HIV-infected individuals. Cells undergoing apoptosis in lymph nodes from HIV-infected individuals do not harbor virus, and therefore a bystander effect has been postulated to mediate apoptosis of uninfected cells. These data raise the possibility that antigen-presenting cells are a source of FasL and that HIV infection of cells such as macrophages may induce or increase FasL expression. In this report, we demonstrate that HIV infection of monocytic cells not only increases the surface expression of Fas but also results in the de novo expression of FasL. Interference with the FasL-Fas interaction by anti-Fas blocking antibodies abrogates HIV-induced apoptosis of monocytic cells. Human monocyte-derived macrophages from healthy donors contain detectable FasL mRNA, which is further upregulated following HIV infection with monocytotropic strains. HIV-infected human macrophages result in the apoptotic death of Jurkat T cells and peripheral blood T lymphocytes. Interruption of the FasL-Fas interaction abrogates the HIV-infected macrophage-dependent death of T lymphocytes. These results provide evidence that human macrophages can provide a source of FasL, especially following HIV infection, and can thus participate in lymphocyte depletion in HIV-infected individuals.

Apoptosis↗
PubMed1996

Infectious rates of central venous pressure catheters: comparison between newly placed catheters and those that have been changed.

OBJECTIVE: To analyze the rate of infection of de novo, guidewire exchanged, and new site replacement catheters in a cohort of patients in whom catheters were changed on the basis of the clinical discretion of the attending physicians. DESIGN: We conducted an observational cohort study in catheterized patients in the intensive-care unit (ICU). MATERIAL AND METHODS: ICU patients admitted between Jan. 1, 1991, and Dec.31, 1992, were eligible for enrollment in the study. Catheter care, replacement, and duration were prospectively documented. Catheter-related infection was prospectively evaluated. Rates of catheter-related infection were determined for de novo, guidewire exchanged, and new site replacement catheters and analyzed relative to the duration of placement of individual catheters and the total duration of central venous catheterization for a specific patient. RESULTS: Fifty catheter-related infections developed in 2,470 patients. When the rate of catheter-associated infection was determined for each type of catheterization, de novo catheters had a lower observed rate of infection than either replacement type (P < or = 0.0001). After controlling for the effect of time, we found that the rate of catheter-related infections associated with a de novo catheter was less than the rate in guidewire exchanged catheters (P = 0.035). Rates of infection were similar between guidewire exchanged catheters and catheters replaced to a new site. CONCLUSION: In a population of ICU patients in whom catheter change was governed by clinical judgement, no differences were noted between the observed rates of infection of new site replacement catheters and guidewire exchange catheters.

Adult↗