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Biomedical subjects

I A Clark

Publications and source records attributed to I A Clark.

At least 73 records · Page 4Linked to original sources
PubMed1987

Inhibition of intra-erythrocytic growth of Plasmodium falciparum by human sera from Papua New Guinea.

Plasmodium falciparum was cultured through a single intra-erythrocytic cycle of growth in the presence of sera from various areas of Papua New Guinea. Of 194 sera tested from healthy individuals or subjects with hyperreactive malarious splenomegaly (HMS), 107 (55%) significantly inhibited parasite development. Inhibition did not correlate with malaria experience or HMS, though it was to some extent a seasonal phenomenon. Sera with inhibitory activity lost this after dialysis. A possible explanation for these findings is the occurrence of a dietary toxin with antimalarial properties detectable in vitro.

Adolescent↗
PubMed1987

Cell-mediated immunity in protection and pathology of malaria.

The stimulation of protective immunity against malaria is the goal of many research groups. But trials with antigens that stimulate antibodies have yet to fulfil these expectations, and it is increasingly recognized that non-antibody-mediated immunity is also important in immunity to malaria - especially through mediators such as gamma interferon, tumour necrosis factor and reactive forms of oxygen. However, the host can suffer if this type of immune response is too exuberant, and in this review, Ian Clark argues that much of what is recognized as clinical malaria is caused in this way. He suggests that only when discussed in these terms can malaria illness and pathology be seen as a coherent, predictable entity instead of a sea of unconnected surprises. Moreover, these ideas have important implications for vaccine development that, although requiring more basic work, must not be neglected.

Journal Article↗
PubMed1987

Antimalarial activity of a riboflavin analog against Plasmodium vinckei in vivo and Plasmodium falciparum in vitro.

The riboflavin analog 10-(4'-chlorophenyl)-3-methylflavin was found to have significant activity against Plasmodium vinckei vinckei when administered orally and parenterally; it was active against P. falciparum in culture. It inhibited mouse erythrocyte glutathione reductase in a dose-dependent manner. When administered orally, 5-deazariboflavin was not active in vivo although it has been shown to have activity against P. falciparum in vitro.

Administration, Oral↗
PubMed1987

Possible roles of tumor necrosis factor in the pathology of malaria.

The authors have earlier proposed that tumor necrosis factor (TNF) might contribute to the pathology of malaria. Here they report the outcome of injecting recombinant human TNF/cachectin into normal mice and others with low parasitemias (6-35%) of Plasmodium vinckei. The object was to see how precisely the pathologic features of the terminal stages of this infection could be produced, when parasitemias are 70-80%. Hypoglycemia, mid-zonal liver damage, and pulmonary accumulation of neutrophils in the pulmonary vasculature, all of which are seen in severe P vinckei infection, occurred within 4-12 hours after the mildly infected mice received TNF/cachectin. Uninfected mice were much less susceptible. TNF/cachectin also increases plasma lactate, a change seen in both the human and rodent diseases. From these findings and the recent literature on TNF/cachectin, including its detection in serum from malarial patients, it seems likely that excessive release of this monokine could account for certain of the unexplained pathologic features of human malaria.

Animals↗
PubMed1986

Effect of antioxidants on primary alloantigen-induced T cell activation and proliferation.

Because oxygen-centered free radicals are involved in cell-mediated immune responses, we examined the possibility that these reactive species could also have a role in the lymphoproliferative response to alloantigens in the mixed lymphocyte culture (MLC). Three classes of agents that prevent the formation, or damaging effects, of oxygen radicals were tested: the non-permeant electron acceptor ferricyanide; the iron chelators desferrioxamine, desferrithiocin, octanohydroxamic acid, and pyridoxal isonicotinoyl hydrazone, which are thought to be capable of preventing the iron-catalyzed reduction of H2O2 to more reactive species; and the lipid-soluble free radical scavenger butylated hydroxyanisole. These compounds inhibited the proliferation of all potential responder cells in the MLC in a dose-dependent manner. Inhibition was observed only if these agents were present early (less than 40 hr) in the MLC; if added later, their effects were significantly reduced. In contrast, the interleukin 2 (IL 2)-dependent proliferation of CTLL-2 cells or Con A blasts was not affected by these compounds at concentrations that inhibited proliferation in MLC by greater than 90%. Interleukin 1 (IL 1) production by peritoneal exudate cells and IL 2 and IL 1 levels in MLC were not affected by any of the agents tested. By flow microfluorometry, the expression of IL 2 receptors on stimulated T cells was found to be inhibited in the presence of these drugs. Taken together, the data point to an important role for free radical-mediated processes during the early stages of T lymphocyte activation, before IL 2 receptor expression.

Animals↗
PubMed1986

Protection of vitamin E from oxidation by increased ascorbic acid content within Plasmodium vinckei-infected erythrocytes.

Erythrocytes isolated from mice at a late stage of infection with the malarial parasite Plasmodium vinckei contained increased levels of vitamin E, but neither control nor infected erythrocytes contained detectable levels of alpha-tocopherolquinone, an oxidation product of vitamin E. Total levels of the antioxidant, vitamin C, were more than doubled in the same populations of highly parasitized erythrocytes. These observations, and the lower ratio of oxidized to reduced forms of ascorbic acid in parasitized compared to nonparasitized erythrocytes, raise the possibility that increased redox-cycling between the two vitamins may account for the failure to detect alpha-tocopherolquinone. Thus, late in infection of mice with the lethal parasite P. vinckei, the content and redox state of erythrocytic ascorbic acid is altered so that it protects vitamin E, and presumably the parasitized red cell and its contents, from oxidative damage.

Animals↗
PubMed1986

Bleomycin-detectable iron in plasma from Plasmodium vinckei vinckei-infected mice.

Plasma from mice heavily parasitized by Plasmodium vinckei vinckei was found to contain micromolar levels of iron as detected by the 'bleomycin assay' (slightly modified) of Gutteridge et al. [(1981) Biochem. J. 199, 263-265]. Uninfected mouse plasma contained little or no bleomycin-detectable iron. Plasma ultrafiltrate from infected mice contained no bleomycin-detectable iron, indicating that such iron was associated with the protein/macromolecule fraction. We speculate that this iron could catalyse reduction of peroxides in vivo and thus play a role in malaria pathology.

Animals↗
PubMed1986

Injection of free radical generators causes premature onset of tissue damage in malaria-infected mice.

Lymphoid and liver damage does not usually occur in Plasmodium vinckei-infected mice until parasitaemias reach 70-80 per cent and the mice are showing signs of illness. We report here that these changes can be induced in mice of healthy appearance and lower parasitaemia by injecting divicine or tertiary-butyl hydroperoxide, two generators of free oxygen radicals. The same or larger doses of these radical generators did not induce this tissue damage in normal mice. Phagocytic leukocytes are activated in P. vinckei-infected mice, and secretion by these cells of toxic oxygen metabolites has been suggested to be part of this process. Additive effects of these free radicals and those generated from divicine and t-butyl hydroperoxide could account for the increased susceptibility of parasitized mice to tissue damage by these agents.

Animals↗
PubMed1986

Increased production of arachidonate metabolites by peritoneal cells of mice infected with Plasmodium vinckei vinckei.

Peritoneal cells from mice infected with Plasmodium vinckei vinckei generate about four times more prostaglandin F and 6-keto prostaglandin F1 alpha, five times the prostaglandin E and ten times the thromboxane B2 than do peritoneal cells from normal mice. These results were not due to differences in the ratios of cell subpopulations from each group. As well as providing additional evidence that macrophage activation occurs in malaria, the increased production of these prostanoids could help explain some of the manifestations of this disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load.

The protection of mouse erythrocytes (RBC) parasitized with Plasmodium vinckei vinckei against activated oxygen species was examined in relation to the intraerythrocytic parasite load. RBC from highly infected animals were separated by density gradient centrifugation into six bands with increasing parasite content and with parasitemias ranging from 17% to 100%. Increase in parasite load was accompanied by a decrease in the activities of the enzymes superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), glutathione peroxidase (EC 1.11.1.9), glutathione reductase [NAD(P)H] (EC 1.6.4.2), and NADH-methemoglobin reductase (EC 1.6.2.2; NADH:ferricytochrome b5 oxidoreductase) in the RBC lysates. In contrast, the total amount of reduced glutathione increased in the highly parasitized bands. Furthermore, the vitamin E content of all RBC bands, including the one that contained mainly nonparasitized erythrocytes, was 3- to 5-fold higher than that of control noninfected RBC. Increasing parasite load was accompanied by an increase in the production of malonyldialdehyde, indicating enhanced lipid peroxidation. Our results indicate that oxidative stress is experienced by all RBC during a malarial infection and is accompanied by a variety of changes in the antioxidant defense mechanisms of the host and the parasite. Furthermore, it appears that the plasma membrane of the host cell is better protected against oxidative injury than are the membranes surrounding the parasite.

Animals↗
PubMed1984

Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent.

Lewis rats that are primed with guinea pig spinal cord homogenized in complete Freund's adjuvant (GPSCH-CFA) develop overt symptoms of experimental allergic encephalomyelitis (EAE). Treatment with the iron-chelating agent, desferrioxamine B mesylate (DFOM), at various times before the onset of EAE, dramatically suppressed both the severity and duration of disease. When DFOM was administered to rats soon after the development of neurological signs, a rapid recovery occurred, though mild, transient symptoms could be seen approximately 1 wk after withdrawal of the drug. Treatment with DFOM was always accompanied by a diminution of T cell responsiveness on the part of the delayed-type hypersensitivity/helper subset and, on histological examination, an absence of inflammatory cells from lesions. Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation. The mechanisms underlying the effect of DFOM on the severity of EAE, and the possible implications for treatment of multiple sclerosis are discussed.

Animals↗
PubMed1984

Proposed treatment of Duchenne muscular dystrophy with desferrioxamine.

The primary disturbance in Duchenne muscular dystrophy (DMD) appears to affect membrane function, and changes characteristic of oxidant-induced damage occur in skeletal muscle and erythrocytes. There is recent evidence that DMD is a functional tocopherol deficiency, with reduced levels of the lipoprotein required to carry tocopherol to tissues. This may explain the parallels between DMD and dietary tocopherol deficiency. Thus DMD should follow the usual experience of other examples of oxidative pathology, where the balance between tocopherol, the main antioxidant in membrane lipids, and non protein-bound iron, an important catalyst of reactions which produce oxidizing free radicals, largely determines whether or not tissue damage occurs. Desferrioxamine prevents oxidant damage in vitro and in vivo by removing this iron, and may therefore be able to reverse the muscle damage of DMD. Recent experience with this drug in long term dialysis patients is consistent with this suggestion.

Animals↗