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Biomedical subjects

Michael M Lederman

Publications and source records attributed to Michael M Lederman.

62 records · Page 4Linked to original sources
PubMed2002

Therapeutic challenges of AIDS-related non-Hodgkin's lymphoma in the United States and East Africa.

Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. As we enter the third decade of the acquired immunodeficiency syndrome (AIDS) epidemic, it is apparent that the evolution of antiretroviral therapy and the emergence of combination antiviral strategies have greatly affected the natural history of HIV infection and its neoplastic complications. For example, there may be a trend for declining incidence of AIDS-related lymphoma in the United States for the first time. However, in regions of the world where the burden of HIV infection is greatest, such as in East Africa, AIDS-related lymphoma is an increasing cause of morbidity and mortality. Treatment of lymphoma has evolved coincident with improvements in antiretroviral therapy. Infusional chemotherapy regimens may offer advantages over other regimens and schedules, but comparative trials have not been done. Clinical trial data are available on which to develop therapeutic strategies to treat this disease in East Africa where pragmatic approaches are needed. Both the differences in manifestations of HIV infection and the inherent difficulties in administering cytotoxic chemotherapy in this part of the world must be taken into consideration in planning therapeutic strategies. Improved understanding of the pathogenesis of HIV infection and lymphoma will likely yield improved therapeutic interventions as well.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Impact of suppression of viral replication by highly active antiretroviral therapy on immune function and phenotype in chronic HIV-1 infection.

We compared immune phenotypes, lymphocyte proliferation (LP), and delayed type hypersensitivity (DTH) responses in 28 male antiretroviral treatment-naive and experienced HIV-1-infected patients, matched pair-wise according to age and CD4+ T-lymphocyte count. Median CD4+ T-lymphocyte counts were 441 cells/microL and 483 cells/microL and median CD4+ T-lymphocyte nadirs were 435 cells/microL and 150 cells/microL in both groups, respectively. Absolute numbers of circulating T-lymphocyte subpopulations and proportions of naive and memory T-lymphocytes were comparable in the two groups. Untreated patients had greater proportions of activated CD4+ (p <.05) and CD8+ (p <.01) T-cells expressing human leukocyte antigen (HLA)DR and CD38 and fewer CD8+ cells expressing CD28 (p <.05). DTH and LP responses were comparable in both groups except for HIVp24, LP responses, and mumps DTH responses, which were of greater magnitude in the group treated with highly active antiretroviral therapy (HAART) (p <.05). Thus, HIV-1-infected patients who experienced substantial increases in CD4+ T-lymphocyte counts after suppression of viral replication on HAART had fewer activated lymphocytes and similar immune function when compared with findings in untreated patients with similar CD4+ T-cell counts. HIV replication has minimal real-time effect on CD4+ T-cell function in response to non-HIV antigens but helper T-cell responses to HIV-gag antigen are impaired during ongoing viral replication and may be restored by antiretroviral therapy.

ADP-ribosyl Cyclase↗
PubMed2002

Close link between CD4+ and CD8+ T cell proliferation defects in patients with human immunodeficiency virus disease and relationship to extended periods of CD4+ lymphopenia.

T cell proliferation failure is commonly associated with human immunodeficiency virus (HIV) infection. By examining T cell function on a single-cell basis, we found that CD4(+) T cell proliferation failure was often accompanied by CD8(+) T cell proliferation defects in patients with HIV disease. The defects are characterized by a proportional failure and reduced efficiency of precursor T cell proliferation after stimulation. In this study, patients who historically had low levels of circulating CD4(+) T cells were most likely to demonstrate cellular proliferation failure, regardless of current CD4(+) T cell counts. In contrast, neither historical nor current plasma HIV RNA levels were predictive of proliferation failure. These results suggest that mechanisms of T cell proliferation failure are more complex than can be explained by the direct effects of HIV replication and that therapeutic intervention to avoid prolonged periods of CD4(+) lymphopenia may be desirable for the preservation of immune function in patients with HIV disease.

CD4 Lymphocyte Count↗
PubMed2002

Placebo-controlled trial of cyclosporin-A in HIV-1 disease: implications for solid organ transplantation.

OBJECTIVE: Earlier open-label clinical trials have provided conflicting data on the effects of cyclosporin-A (CsA) on the clinical course and immune status of patients with HIV disease. With the prospects for wider use of CsA in the setting of solid organ transplantation in HIV-infected persons, data on the safety and immunologic activity of this agent are needed. We report here the results of a randomized, double-blind, placebo-controlled trial to assess the safety and immunologic activity of CsA administration in early HIV disease. METHODS: Twenty-eight patients with confirmed HIV infection, CD4 cell counts greater than 500 x 106/L, and plasma HIV RNA >600 copies/mL were randomized to receive 2 mg/kg of CsA (Neoral) twice daily or identical placebo for 12 weeks. Subjects were stratified for the presence or absence of stable concomitant antiviral therapy. The primary end point was the effect of therapy on immune activation as assessed by the levels of soluble interleukin-2 receptors. Secondary end points included safety and effects of treatment on plasma HIV RNA, CD4 cell count, and other markers of immune activation and function. RESULTS: The low dose of CsA used in this study did not suppress immune activation or increase circulating CD4 cell counts. Delayed-type hypersensitivity responses were not affected; however, lymphocyte proliferative responses tended to decrease. CsA-treated patients experienced a small but significant rise in plasma HIV RNA levels. CONCLUSIONS: Low-dose CsA has no benefit in patients with stable early HIV disease, and its administration may be associated with an increase in plasma HIV RNA. The use of CsA in HIV-infected patients undergoing organ transplantation should be undertaken with caution

Adult↗
PubMed2002

[Manifestation of hyper-IgE syndrome in advanced HIV-1 infection].

BACKGROUND: The classical triad of Job's syndrome (Hyper-IgE syndrome), a congenital immunodeficiency disorder, includes recurrent "cold" abscesses, pneumonias and extreme elevations of the serum IgE concentration. CASE REPORT: A 49-year-old HIV-1 infected patient with a viral load of 268,852 copies/ml plasma and a CD4+ T lymphocyte concentration of 2 cells/microliter blood was admitted to our clinic for antibiotic therapy and incision and drainage of several large abscesses. The patient suffered for approximately 5 years from recurrent pneumonias, abscesses and multiple allergies. The serum IgE level was over 100-fold elevated and, after analysis of archived serum samples, had not been influenced by fluctuations in the plasma viral load or changes in the CD4+ T lymphocyte concentration in previous years. No stigmata of Job's syndrome were present prior to the patient's HIV-1 infection. Observations on other patients with AIDS and recurrent abscesses suggest that in these patients hyperimmunoglobulinemia E is related to a cytokine class switch from a TH1 to a TH2 profile as CD4+ T lymphocytes are depleted. CONCLUSIONS: Following CD4+ T lymphocyte depletion, it has been rarely documented that HIV-1 infected patients may develop clinical symptoms and a hyperimmunoglobulinemia E, similar to patients with the congenital immunodeficency of Job's syndrome.

Abscess↗
PubMed2002

CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection.

To evaluate the effects of the timing of highly active antiretroviral therapy (HAART) on immune reconstitution, we compared lymphocyte subpopulations and lymphocyte proliferation (LP) in response to Candida albicans, cytomegalovirus, HIV p24, Mycobacterium avium complex, pokeweed mitogen, streptokinase, and tetanus toxoid in 43 patients with pretherapy advanced, moderately advanced, and early chronic HIV-1 infection. All patients had recent CD4+ T-cell counts >450/microl and HIV RNA <400 copies/ml for >12 months. CD4+ nadirs were positively correlated with recent numbers of CD4+ T-cells (P < 0.001), memory cells (P < 0.001), and naïve CD4+ T-cells (P < 0.05) and CD4+ CD28+ T-lymphocytes (P < 0.05) and were negatively correlated with recent CD8+ T-lymphocyte counts (P < 0.05). Only CD4+ naïve T-cells normalized when HAART was initiated at lower CD4+ T-cell levels. Fifty-three percent of patients had LP responses to HIV p24 antigen. While LP responses to prevalent antigens were usually present, responses to tetanus toxoid were more common with higher CD4+ T-lymphocyte nadirs (P < 0.05). Delaying HAART may limit phenotypic and functional immune restoration in HIV-1 infection.

Adult↗
PubMed2002

High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia.

Lactic acidosis is the most dramatic manifestation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction. The optimal management of subjects who recover from an episode of lactic acidosis--or its milder form, symptomatic hyperlactatemia--remains unclear. Most physicians opt to restart NRTI-sparing regimens, but such an option may not be available for heavily antiretroviral-experienced patients. Therefore, there is a need to investigate ways to prevent the recurrence of hyperlactatemia in patients who require NRTI-based therapy.

Acidosis, Lactic↗