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Biomedical subjects

M M Lederman

Publications and source records attributed to M M Lederman.

At least 73 records · Page 4Linked to original sources
PubMed1997

CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects.

We examined the relationships among CD4+-T-cell counts, spontaneous apoptosis, and Fas expression among peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1 (HIV-1)-infected patients. After 2 days of incubation, propidium iodide DNA staining and flow cytometry revealed that peripheral blood mononuclear cells from subjects with the lowest CD4+-cell numbers (0 to 99/microl; n = 20) showed the highest frequency of apoptosis: 22.4% +/- 2.7% (mean +/- standard error) versus 13.8% +/- 1.2% and 12.7% +/- 1.4% among peripheral blood mononuclear cells obtained from patients with 100 to 499 CD4+ cells/microl (n = 19) and >500 CD4+ cells/microl (n = 17), respectively. Each of these means differed significantly from the mean frequency of apoptosis (6.3% +/- 0.7%) of peripheral blood mononuclear cells obtained from HIV-1-seronegative controls (P < 0.001, Student's t test). After incubation, the percentage of peripheral blood mononuclear cells expressing Fas antigen was increased for the HIV-1-infected subjects, and this was most evident for patients with more advanced disease. Among patients with fewer than 100 CD4+ cells/microl, 64.4% +/- 5.4% of peripheral blood mononuclear cells were Fas+, as opposed to 25.8% +/- 3.0% and 14.5% +/- 1.7% Fas+ cells among patients with more than 100 CD4+ cells/microl and healthy controls, respectively (P < 0.05 for each group comparison). Interestingly, in all populations, most apoptotic cells did not express Fas. Thus, apoptosis and Fas expression are increased in incubated peripheral blood mononuclear cells obtained from HIV-1-infected patients and these phenomena are enhanced as disease progresses.

Apoptosis↗
PubMed1996

A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team.

BACKGROUND: This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter. METHODS: We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death. RESULTS: Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment. CONCLUSIONS: Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Activation of antigen-induced lymphocyte proliferation by interleukin-15 without the mitogenic effect of interleukin-2 that may induce human immunodeficiency virus-1 expression.

The newly identified cytokine, IL-15 enhanced antigen-induced proliferation of PBMC obtained from HIV-1-seropositive subjects. When compared to IL-2 which enhanced both spontaneous and antigen-induced lymphocyte proliferative responses, IL-15 rarely increased spontaneous lymphocyte proliferation. Additionally, in cultures of lymphocytes obtained from 15 HIV-1-infected patients with < 300 circulating CD4- lymphocytes/microliter IL-15 induced significant HIV-1 expression (46, 21, and 71 pg/ml) in only 3 of 15 experiments and IL-2 induced significant HIV-1 expression (range 16- > 5000 pg/ml) in 11 of 15 experiments (P < 0.01, Fischer's exact test). Simultaneous assays of cytokine-induced spontaneous lymphocyte proliferation and HIV-1 expression revealed similar dose-response relationships for induction of HIV-1 and lymphocyte proliferation by IL-2. Thus, IL-15 helps to correct the impaired proliferative response of CD4+ lymphocytes from HIV-1-infected persons without the mitogenic effect of IL-2 that also may induce HIV-1 expression.

Adult↗
PubMed1996

HIV-1 Tat protein and its inhibitor Ro 24-7429 inhibit lymphocyte proliferation and induce apoptosis in peripheral blood mononuclear cells from healthy donors.

To explore further the effects of the HIV-1 transactivator protein Tat on human lymphoid cell function we examined the effects of Tat on lymphocyte proliferation and programmed cell death (apoptosis). We found that the HIV-1 Tat protein induced apoptosis and inhibited lymphocyte proliferative responses in lymphocytes obtained from healthy HIV-1 seronegative donors. Surprisingly, the Tat inhibitor Ro 24-7429 also induced apoptosis and inhibited antigen-induced lymphocyte proliferation. In checkerboard experiments, each agent could antagonize the effects of the other in both assays. These data suggest that Tat and its inhibitor may interact with a host element critically important in the processes of lymphocyte proliferation and programmed cell death. The HIV-1 Tat protein may affect both lymphocyte survival and function in HIV-1 infection, thereby contributing to the immune deficiency of HIV-1 disease.

Antiviral Agents↗
PubMed1996

Human immunodeficiency virus type 1 activation after blood transfusion.

BACKGROUND: Anemia and transfusion are predictors of disease progression in AIDS patients. This study was designed to examine the effects of blood transfusion on human immunodeficiency virus type 1 (HIV-1) expression. STUDY DESIGN AND METHODS: Assays of plasma viral load were performed before and after transfusion in nine HIV-1-infected patients who required blood transfusion for refractory anemia. RESULTS: There was a modest rise in plasma HIV-1 p24 antigen and plasma HIV-1 RNA beginning 1 to 2 weeks after the blood transfusion. The mean change in plasma p24 antigen for all patients was 9.3 +/- 5.1 (mean +/- SE) pg per mL at Week 2 after transfusion and 18 +/- 11.1 pg per mL at Week 4. Plasma HIV-1 RNA levels were unchanged immediately after transfusion and exceeded pretransfusion levels with a mean rise of 84 +/- 40 percent (SE) at Week 1, 70 +/- 27 percent at Week 2, and 67 +/- 38 percent at Week 4 (p = 0.006, exact permutation test). There was no increase in spontaneous or interleukin 2-induced lymphocyte proliferation or p24 antigen production by patients' lymphocytes that were examined immediately after blood transfusion. CONCLUSION: The transfusion of blood to persons with advanced HIV-1 infection modestly increases plasma levels of HIV-1. The activation of HIV-1 expression by transfusion may help to explain the accelerated course of HIV-1 disease in recipients of blood transfusion.

Anemia↗
PubMed1996

Detection of apoptotic cells by selective precipitation of [3H]thymidine-labelled DNA.

Apoptosis is characterized by systematic fragmentation of high-molecular-weight DNA into oligonucleosome fragments. A sensitive method for detection of apoptotic cells involving [3H]thymidine-labelled DNA is presented. Cells from mid-log-phase cultures were labelled with [3H]thymidine for 15 to 18 h and then exposed to gamma irradiation to induce apoptosis. A modified Hirt method was used to separate low-molecular-weight DNA from high-molecular-weight DNA. The percentage of fragmented DNA and high-molecular-weight DNA were measured by scintillation spectrometry. This method was compared with an established flow cytometric method for detection of apoptotic cells by using propidium iodide staining of DNA. We observed a good correlation between these two methods in detecting apoptosis. Hence, expensive flow cytometric assays for detection of apoptosis in dividing cells may be replaceable by a method involving [3H]thymidine labelling of DNA and separation of low-molecular-weight DNA from high-molecular-weight DNA by precipitation.

Apoptosis↗
PubMed1996

A predictive model to identify Clostridium difficile toxin in hospitalized patients with diarrhea.

OBJECTIVES: Although Clostridium difficile is a common pathogen in hospitalized patients with diarrhea, no study has attempted to develop a predictive model to estimate the likelihood of C. difficile positivity. METHODS: We conducted a cross-sectional study at a single hospital of 271 patients with diarrhea for whom stool was tested for C. difficile toxin. The sample was randomly divided into a subset to derive the model (n = 180) and another to validate it (n =91), and independent predictors of toxin positivity were identified using logistical regression analysis. RESULTS: C. difficile toxin was present in 81 patients and absent in 190. In the derivation set, a positive toxin was independently predicted (p < 0.0005) by readmission within 2 wk of prior hospitalization, by a white blood cell count > or = 10,000/mm3, and by presence of fecal leukocytes. In the validation set, C. difficile toxin was present in 24, 29, and 77% of patients with 0, 1, and > or = 2 risk factors, respectively. CONCLUSION: If validated prospectively and/or other centers, the model could identify patients who should be considered for empirical management while awaiting results of toxin assays.

Aged↗
PubMed1995

Host-directed and immune-based therapies for human immunodeficiency virus infection.

This essay reviews the rationale underlying host-directed or immune-based therapeutic strategies for human immunodeficiency virus (HIV) infection and its complications. These approaches have seen only limited trial in the past 10 years, but as more is learned about the immunopathogenesis of HIV disease and as the limitations of virus-directed therapies become more apparent, the need to pursue other therapeutic avenues has become increasingly important. Moreover, properly designed trials of host-directed and immune-based therapies can provide key insights into the pathogenesis of HIV disease that may be otherwise unattainable through in vitro studies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

L-2-oxothiazolidine-4-carboxylic acid (procysteine) inhibits expression of the human immunodeficiency virus and expression of the interleukin-2 receptor alpha chain.

These studies were undertaken to examine the in vitro effects of the cysteine pro-drug L-2-oxothiazolidine-4-carboxylic acid (Procysteine) on human immunodeficiency virus expression. Procysteine inhibited HIV expression in human peripheral blood mononuclear cells as detected by measurement of supernatant core antigen. In transient transfection assays, Procysteine inhibited gene expression controlled by the HIV-1 promoter in activated Jurkat cells but not in resting Jurkat cells. Gel-shift assays showed that Procysteine inhibited NF-kappa B DNA binding activity in nuclear extracts. Procysteine did not affect the production of interleukin-2 by peripheral blood mononuclear cells of healthy HIV-seronegative subjects, as measured by bioassay but it decreased the density of cell-surface interleukin-2 receptors detected by flow cytometry after stimulation with phytohemagglutinin (PHA). Thus, Procysteine inhibits HIV expression, HIV promoter activity, and NF-kappa B binding activity in vitro. Procysteine does not affect interleukin-2 production but inhibits interleukin-2 receptor expression in PHA-stimulated peripheral blood mononuclear cells.

Cells, Cultured↗
PubMed1995

HIV type 1 Tat protein induces apoptosis and death in Jurkat cells.

Jurkat cells stably expressing high levels of the HIV-1 Tat protein were generated after transfection with an Epstein-Barr virus-based episomal replicon and selection in hygromycin B. The Jurkat Tat transfectants exhibited a longer doubling time when compared to Jurkat cells or Jurkat cells transfected with the control parent plasmid. Cell cycle analysis revealed comparable durations of each phase of the cell cycle in the Tat and control transfectants. Flow cytometric analysis using Hoechst 33342 and propidium iodide staining revealed that the Tat transfectants exhibited a higher percentage of apoptotic cells when compared to the control transfectants (29.1 +/- 3.1 vs. 11.43 +/- 3.1%). Incubation of Jurkat cells with recombinant HIV-1 Tat protein resulted in induction of apoptosis. The HIV-1 Tat protein induces apoptosis in a CD4-positive T cell line. Tat-induced programmed cell death may contribute to the lymphocyte depletion seen in persons infected with HIV-1.

Apoptosis↗
PubMed1995

High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.

Tumor necrosis factor-alpha (TNF) may activate human immunodeficiency virus (HIV), antagonize zidovudine activity, and contribute to AIDS wasting syndrome. Pentoxifylline decreases TNF production. In cell culture, pentoxifylline decreases HIV replication and gene expression. Since an AIDS Clinical Trial Group study suggested that pentoxifylline (400 mg thrice daily) is safe in AIDS patients and decreases TNF mRNA levels in peripheral blood mononuclear cells (PBMC), a second cohort received 800 mg thrice daily for 8 weeks. During treatment, the median decrease in TNF production by PBMC cultured with 0.1 microgram/mL lipopolysaccharide (LPS) was 40%. The median change in TNF mRNA was a 34% decrease. Pentoxifylline did not affect HIV levels as detected by quantitative microculture or serum p24 antigen measurements, nor did it alter zidovudine pharmacokinetics. The most common toxicity was gastrointestinal. Pentoxifylline at dosages of less than thrice-daily 800 mg is well tolerated and may decrease TNF mRNA levels and LPS-induced TNF production.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Human immunodeficiency virus (HIV) type 1 infection status and in vitro susceptibility to HIV infection among high-risk HIV-1-seronegative hemophiliacs.

Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.

Adult↗
PubMed1995

A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team.

Ro 24-7429, a Tat antagonist, dosed at 75, 150, or 300 mg/day, was compared with nucleoside analogue (zidovudine or didanosine) for 12 weeks in 96 human immunodeficiency virus (HIV)-infected patients to assess safety and activity. The primary adverse effect of Ro 24-7429 was rash, which necessitated treatment discontinuation in 6 of 71 patients. Nucleoside analogue treatment produced an average increase in CD4 cell count of 28 cells/mm3 at week 8 versus a decrease of 27 cells/mm3 in recipients of Ro 24-7429 (P < .001). Serum HIV p24 antigen levels decreased by an average of 111 pg/mL in nucleoside recipients at week 8 compared with an increase of 41 pg/mL in recipients of Ro 24-7429 (P = .007). Nucleoside-treated patients had a mean 0.66 log10 reduction in infectious peripheral blood mononuclear cells, while Ro 24-7429 recipients had a mean 0.02 log10 reduction (P = .02). No dose-response relationships were observed in the Ro 24-7429 groups. In this study, Ro 24-7429 treatment showed no evidence of antiviral activity.

Adult↗
PubMed1995

Pentoxifylline for the treatment of HIV infection and its complications.

The increased levels of tumor necrosis factor-alpha (TNF-alpha) seen in patients with acquired immune deficiency syndrome (AIDS) may contribute to the AIDS-related wasting syndrome. TNF also induces expression of human immunodeficiency virus (HIV) through activation of the transcription factor NF-kappa B, which binds to the viral long terminal repeat (LTR). Because TNF can decrease the antiretroviral activity of zidovudine (AZT) in vitro, pentoxifylline (PTX) may increase the efficacy of AZT. PTX decreases HIV replication in acutely infected cells and inhibits gene expression controlled by the HIV-1 LTR. The antiretroviral activity of PTX is associated with decreased binding of NF-kappa B to its recognition sequences. Therefore, PTX may inhibit HIV expression indirectly by diminishing TNF production and directly, by decreasing activity of NF-kappa B. PTX, and an inhibitor of the viral transactivator TAT, Ro24-7429, may inhibit HIV gene expression in a cooperative fashion. The first clinical study of PTX in AIDS patients was conducted by us through the AIDS Clinical Trial Group of the National Institutes of Health. AIDS patients on antiretroviral therapy received PTX 400 or 800 mg three times daily for 8 weeks. TNF assays included TNF mRNA levels in peripheral blood mononuclear cells (PBMCs) and inducible TNF protein levels in the supernatant of PBMCs cultured in the presence of 0.1 microgram/ml lipopolysaccharide (LPS). The median change in TNF mRNA was a 30% decrease. There was a median and significant 40% decrease in the production of inducible TNF protein. HIV load decreased in 10 patients and increased in four patients, but did not change in the group as a whole. Others have extended our initial observations in HIV-infected patients. In a placebo-controlled trial, TNF production by unstimulated PBMCs decreased by 52% in the PTX arm and increased by 7.2% in the placebo arm. In a study comparing AZT, PTX, or a combination of the two, viral load after treatment was ninefold above baseline in the AZT or PTX alone arm, compared to only twofold in the combination arm. In a quality of life trial, PTX was associated with improvement in depression, anger, and social and cognitive function: a placebo effect, however, was not ruled out. PTX 400 mg three times daily is safe and well tolerated. PTX decreases PBMC TNF expression in HIV-infected patients, measured as protein in culture supernatant or as mRNA, and may decrease viral replication. Further studies of HIV-infected persons are needed to ascertain the benefit of PTX as an adjunct either to inhibitors of reverse transcriptase (e.g., AZT) or of transcription (e.g., TAT inhibitor).

Animals↗
PubMed1994

Reuse of syringes.

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Disposable Equipment↗
PubMed1994

Mycobacterium tuberculosis and its purified protein derivative activate expression of the human immunodeficiency virus.

To examine the effects of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) expression, the monocytoid cell line U1 containing integrated provirus was incubated with the H37Ra strain of M. tuberculosis. This resulted in heightened expression of virus in supernatant that was partially inhibited by antibody to tumor necrosis factor-alpha (TNF-alpha). Purified protein derivative (PPD) prepared from M. tuberculosis also could activate HIV expression, and this was less affected by anti-TNF antibody. PPD could activate the HIV promoter in both U937, the monocytoid cell line from which U1 was derived, and Jurkat, a CD4+ lymphoid line. Activation was abolished by mutations in the nuclear factor (NF)-kB binding domains. Jurkat cells transfected with a plasmid construct linking 8 NF-kB binding domains to the chloramphenicol acetyltransferase (CAT) gene showed increased activity of the reporter gene after activation with PPD. Transcriptional activation of HIV expression by mycobacteria and mycobacterial products may enhance propagation of HIV in monocytoid and lymphoid cells. This may result in accelerated HIV disease progression in persons coinfected with M. tuberculosis.

Base Sequence↗