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Biomedical subjects

D Schwartz

Publications and source records attributed to D Schwartz.

At least 19 recordsLinked to original sources
PubMed1992

Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines.

The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS Vaccines↗
PubMed1992

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

A series of bicyclams have been shown to be potent and selective inhibitors of human immunodeficiency virus (HIV). The compounds are inhibitory to the replication of various HIV-1 and HIV-2 strains in various human T-cell systems, including peripheral blood lymphocytes, at 0.14-1.4 microM, without being toxic to the host cells at 2.2 mM. The bicyclam JM2763 is active against 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant HIV-1 strains and acts additively with AZT. Mechanism of action studies revealed that the bicyclams (i.e., JM2763) interact with an early event of the retrovirus replicative cycle, which could be tentatively identified as a viral uncoating event.

Antiviral Agents↗
PubMed1992

Humanization of immunotoxins.

The construction and expression of a chimeric gene encoding a mouse/human antibody to the human transferrin receptor fused to the gene for angiogenin, a human homolog of pancreatic RNase, are described. F(ab')2-like antibody-enzyme fusions were prepared by linking the gene for human angiogenin to a chimeric anti-transferrin receptor heavy chain gene. The antibody-enzyme fusion gene was introduced into a transfectoma that secretes the chimeric light chain of the same antibody, and cell lines were cloned that synthesize and secrete the antibody-enzyme fusion protein of the expected size at a concentration of 1-5 ng/ml. Culture supernatants from clones secreting the fusion protein caused inhibition of growth and protein synthesis of K562 cells that express the human transferrin receptor but not toward a non-human-derived cell line that lacks this receptor. Whereas excess antibody to the same receptor did not itself inhibit protein synthesis, it was able to completely prevent the protein synthesis inhibition caused by the fusion protein. These results indicate that the cytotoxicity is due to a transferrin receptor-mediated mechanism involving the angiogenin portion of the fusion protein and demonstrate the feasibility of constructing recombinant antibody-RNase molecules capable of killing tumor cells bearing the transferrin receptor. The significance of the acquired cytotoxicity of a mouse/human chimeric antibody linked to a human protein may bear importantly in human therapeutic strategies that use mouse antibodies linked to toxins from plants or bacteria to target tumor cells. It is expected that the humanization of immunotoxins will lead to less toxicity and immunogenicity than currently available reagents.

Animals↗
PubMed1992

Androgenic-anabolic steroid abuse and platelet aggregation: a pilot study in weight lifters.

The abuse of anabolic-androgenic steroids by athletes has recently been associated with the development of myocardial infarction and stroke. Because platelets play a pathogenic role in these disorders, the authors hypothesized that androgenic steroid abuse among weight lifters was associated with increased platelet aggregation as measured in vitro. Twenty-eight study participants were recruited. Twelve denied current androgen use. However, 8 of these 12 tested positive for urinary androgens. Nonsignificant trends toward increased platelet counts and increased platelet aggregation to adenosine diphosphate were noted when androgen users were compared to nonusers. However, when stratified by age, older (greater than 22 years) androgen users required lower concentrations of collagen to produce 50% aggregation of test platelets than did younger (less than or equal to 22 years) androgen users (1.47 versus 3.35 micrograms/ml; p = .01). Further subgroup analysis revealed nonsignificant trends toward increased adenosine diphosphate-induced aggregability and nonsignificant trends in the platelet count in older weight lifters. Subsequent studies using collagen threshold aggregometry revealed no age-dependent effect in 17 other men (aged 18 to 46 years) not specifically selected for activity (r = .17). This study suggests an association between androgen use, age, and increased platelet sensitivity to collagen in weight lifters and may be helpful in explaining recent thrombotic disease in androgen users. It additionally calls into question the validity of subjective reporting when assessing androgen use among weight lifters.

Adolescent↗
PubMed1992

Disseminated intravascular coagulation with renal and liver damage as the predominant manifestations of recurrent relapses in systemic juvenile rheumatoid arthritis.

Relapses of systemic juvenile rheumatoid arthritis associated with intravascular coagulation are rare. This paper describes a patient who, over a two year period, had two relapses, each accompanied by evidence of liver and renal damage and disseminated intravascular coagulation. The patient was not receiving non-steroidal anti-inflammatory drugs, and all laboratory and clinical manifestations of her disease rapidly resolved after treatment with prednisone. It is therefore believed that the hepatocellular damage, in addition to the disseminated intravascular coagulation, was a direct manifestation of disease activity. A possible pathogenic role for tumour necrosis factor is suggested.

Adult↗
PubMed1992

Combined effect of captopril and aspirin in renal hemodynamics in elderly patients with congestive heart failure.

Captopril and aspirin have been claimed to adversely affect renal function. This study was designed to evaluate the safety of concomitant administration of both drugs in patients with moderate to severe congestive heart failure (CHF). The study group consisted of 10 patients with a mean age of 77.6 +/- 4.4 years and a mean New York Heart Association functional class of 2.6 +/- 0.5. Captopril was administered in a rapidly escalating dose regimen over a 4-day period to a maximum dose of 75 mg/day. Aspirin 0.25 g/day was added from day 5 on. Renal plasma flow (RPF) was measured by iodohippurate scan and the creatinine clearance test (Ccr) was used as an index of glomerular filtration rate (GFR). Both Ccr and RPF remained unchanged throughout the study period; 48.9 +/- 16; 48.2 +/- 16.5; 49.4 +/- 16, and 222 +/- 67, 241 +/- 97, 237 +/- 88 ml/min, for days 0, 4, 9, respectively. Only 1 patient developed a significant decrease in Ccr following the administration of captopril. This patient had a further decrease when aspirin was added. The decrease in Ccr was accompanied by a marked reduction in filtration fraction and in mean arterial pressure. Our data suggest that the administration of aspirin to elderly patients with moderate CHF treated with captopril is relatively safe and is not associated with further deterioration in renal function.

Aged↗
PubMed1992

[Immunologic factors in habitual abortion].

Recent advances in immunology have discovered two immunological factors in part of the patients with habitual first-trimester abortions. Antibody formation against the major histocompatibility antigens (HLA = human leukocyte antigen) which can be demonstrated during normal pregnancy is often not detectable in these patients, sometimes presumably because of compatibility in the HLA antigens between mother and fetus. In a high percentage of these patients immunotherapy by subcutaneous leukocyte injections can lead to antibody formation and successful pregnancy. As another immunological factor, a genetic variant of the complement-inactivating leukocyte differentiation antigen CD46 (= TLX antigen, = membrane cofactor protein) could be identified, which can be seen more frequently in patients with habitual abortions as compared to healthy controls. Both factors seem just to contribute to a predisposition for early-pregnancy abortions rather than to be an absolute barrier, as they can also be seen in normal pregnancy and successful carriages can also occur without any therapy in early-pregnancy aborters with an immunological background.

Abortion, Habitual↗
PubMed1992

Erythropoietin therapy obviates the need for recurrent transfusions in a patient with severe hemolysis due to prosthetic valves.

Erythropoietin has been proved extremely effective in ameliorating the anemia of chronic renal failure and is currently under intensive investigation. We describe a patient with severe anemia and secondary hemochromatosis due to prosthetic valves, who has been successfully treated with erythropoietin. During 12 months' follow-up, an acceptable hemoglobin level was maintained without any need for blood transfusions; in addition, there was evidence indicating regression of hemochromatosis. This patient illustrates that erythropoietin therapy might prove beneficial for similar cases.

Anemia, Hemolytic↗
PubMed1992

Energy demands for walking in dysvascular amputees as related to the level of amputation.

Cardiac function and oxygen consumption were measured in 25 patients who underwent amputation for peripheral vascular disease (PVD), and in five similarly aged control patients with PVD. Five patients at each of the midfoot, Syme's, below-, through-, and above-knee amputation levels and the five controls were measured at rest, normal walking speed, and maximum walking speed on a treadmill. At normal walking speed, all of the patients functioned at approximately 80% of their cardiac capacity. Normal walking speed and cadence decreased and oxygen consumption per meter walked increased with more proximal amputation. The ratio of cardiac function and oxygen consumption at normal walking speed as compared with at rest increased with more proximal amputation, and the capacity to increase walking speed and oxygen consumption lessened. Our results suggest that peripheral vascular insufficiency amputees function at a level approaching their maximum functional capacity. At more proximal amputation levels, the capacity to walk short or long distances is greatly impaired.

Amputation, Surgical↗
PubMed1992

Immune-haemolytic anaemia (IHA) after solid organ transplantation due to rhesus antibodies of donor origin: report of 5 cases.

During a 3-year period we observed 5 patients who developed IHA after transplantation of solid organs (4 kidneys, 1 liver) due to irregular anti-erythrocyte antibodies of donor origin (4 times anti-D, once anti-D+C). The onset of acute haemolysis was usually within 2-3 weeks after transplantation; however, 1 patient developed acute haemolysis as late as day 116 after renal transplantation. The course of the clinical and serological signs (DAT positive, 'auto'-antibodies in serum and eluate) was typical and self-limited in all cases, the function of the transplanted organ was usually not affected. All patients could be managed by transfusion of antibody-compatible blood. The administration of azathioprine (1 case) did not seem to have any beneficial effect. The causative antibodies could be demonstrated retrospectively in the serum of 1 donor. Another donor had no detectable irregular anti-erythrocyte antibodies at the time of transplantation, suggesting a secondary immune response of transplanted lymphatic tissue in this case. Both recipients of a kidney from this donor developed IHA. Serum samples of the 2 other donors were not available for investigation. We suggest that a sensitive screening for irregular anti-erythrocyte antibodies in the donor's serum should be performed before any transplantation of solid organs. If such antibodies are found, organs should only be used after irradiation. However, as our experiences show, this cannot prevent IHA in each case. Once haemolysis develops, the correct serological diagnosis and the transfusion of antibody-compatible red blood cells are most important.

Anemia, Hemolytic, Autoimmune↗
PubMed1992

Case report: acute renal failure, thrombocytopenia and nonhemolytic icterus probably caused by mefenamic acid (Parkemed)-dependent antibodies.

A 65-year-old, previously healthy man developed acute renal failure, severe thrombocytopenia and hepatic icterus after a small dose of mefenamic acid (Parkemed). Drug-dependent antibodies reacting against platelets could be identified as the most probable cause for this acute and rapidly reversible disorder. A concomitant hemolytic reaction was not observed and accordingly no drug-dependent red cell antibodies could be demonstrated. The drug-specific antibodies were found only during the acute phase using the platelet immunofluorescence test and a solid-phase immunoassay but not with the monoclonal antibody specific immobilization of platelet antigens assay. After discontinuation of the drug the patient steadily improved and fully recovered until day 22 after admission and drug removal. The clinical course strongly suggests that drug-dependent antibodies against mefenamic acid and/or its metabolites reacting by immune complex mechanism were responsible not only for the thrombocytopenia but also for the renal and hepatic failure.

Acute Kidney Injury↗
PubMed1992

A cascade model for restenosis. A special case of atherosclerosis progression.

BACKGROUND: Restenosis presently limits the long-term success of percutaneous transluminal coronary angioplasty (PTCA) and allied treatments of atheroma. Current views of the pathophysiology of restenosis fail to explain certain important clinical features: Thrombosis, often invoked as a cause of smooth muscle proliferation, wanes before intimal thickening peaks. Prolonged antithrombotic therapy does not eliminate restenosis after PTCA. Furthermore, only a minority of angioplastied lesions develop clinically significant restenosis. METHODS AND RESULTS: We propose a cytokine-growth factor cascade mechanism of restenosis pathobiology that could explain these features of human restenosis. According to this model, PTCA would produce acute local thrombosis and/or mechanical injury that triggers cytokine/growth factor gene expression by resident macrophages and smooth muscle cells. This early acute generation of cytokines could evoke a secondary growth factor and cytokine response that might establish a positive, self-stimulatory autocrine and paracrine feedback loop that would serve to amplify and sustain the proliferative response. This multistage schema would account for the lag between injury and restenosis and the failure of chronic antithrombotic therapy to prevent this process. Human atheromata contain variable numbers of macrophages. The macrophage content of a particular lesion could determine in part propensity to develop restenosis after angioplasty, explaining why all lesions do not develop this process. CONCLUSIONS: Several experimental observations support this novel mechanistic model. Leukocytes and smooth muscle cells express genes for cytokines and growth factors, and products of coagulation and thrombosis can activate mononuclear phagocytes. Cytokines and growth factors often augment their own gene expression and induce one another, providing a potential intralesional amplification loop. Experimental atheroma and advanced human atherosclerotic lesions do not express high levels of growth-stimulatory cytokines such as interleukin-1 or tumor necrosis factor in the basal state but exhibit inducible expression in response to an injurious stimulus. Thus, cascades of autocrine or paracrine mediators whose expression is triggered by vascular injury might contribute to deranged smooth muscle behavior during restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1992

Sclerochoroidal calcification.

We studied 19 patients with sclerochoroidal calcification. The findings were bilateral in 16 patients and unilateral in the remaining three patients. The lesions, which were usually multifocal, had two characteristic appearances, plaque-like and tumorlike. Eleven patients had relatively flat, irregularly shaped, plaque-like, yellow-white lesions located between the arcades and the equator. Eight patients had more elevated tumorlike lesions, ranging up to 6 mm in height. All showed patterns on echography consistent with calcification. The calcification was often documented in both the choroid and sclera; sometimes it appeared only in the choroid, but never only in the sclera. Calcium metabolism appeared to be normal in all but two of the nine patients in whom it was investigated. Idiopathic sclerochoroidal calcification has a characteristic echographic and ophthalmoscopic appearance and may be more common than has been realized.

Aged↗