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Biomedical subjects

I A Clark

Publications and source records attributed to I A Clark.

117 records · Page 7Linked to original sources
PubMedDate not supplied

Roles of tumour necrosis factor in the illness and pathology of malaria.

Evidence is accumulating that the illness and pathology observed in malaria are not caused directly by parasite products, but by normal components of the immune response, mainly monokines such as tumor necrosis factor (TNF), produced in excess. These mediators are released from the host's monocytes and macrophages, apparently in response to stimulation by parasite products. Recombinant TNF, if injected into a range of animal species or into tumour patients, is demonstrably toxic, giving rise to changes typical of acute malaria, and several groups have detected circulating TNF in serum from patients acutely ill with malaria. The short serum clearance time of TNF and TNF tolerance have to be considered when interpreting such data. Current studies indicate that some malarial antigens, in the absence of lipopolysaccharide, can trigger release of TNF. This and other monokines could contribute to cerebral malaria in at least 2 ways: by increasing thrombospondin secretion, and hence favouring local sequestration of knob-bearing parasitized red cells, and, as has been demonstrated in clinical trials in tumour patients, by causing neurological symptoms directly. In addition, it seems that TNF does not act alone, but as part of an interdependent synergizing network of polypeptide mediators. These evidently act together to induce secretion of other cell products, such as platelet-activating factor, prostaglandins, reactive oxygen species and procoagulant activity, that actually cause illness, biochemical change and tissue damage. Understanding these processes should lead to a range of new therapeutic interventions.

Animals↗
PubMedDate not supplied

Serum tumor necrosis factor associated with malaria in patients in the Solomon Islands.

There is now significant evidence that tumor necrosis factor (TNF) is involved in the pathogenesis of malaria. We have tested sera from patients presenting with a febrile illness admitted to hospital in Honiara, Solomon Islands, for the presence of TNF, interferon-gamma, and interleukin-1 (IL-1). This study differs from previous reports as the subjects were mainly adults from a semi-immune population living in an endemic area. The results from 2 different commercially-available assays for TNF were compared, and one was found to be superior to the other. Serum TNF concentrations correlated with malarial parasite density and the patients' temperatures, but not with interferon or IL-1. The results are discussed in the context of the immunopathology of this disease.

Adolescent↗
PubMedDate not supplied

Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology.

The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lymphotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.

Adolescent↗
PubMedDate not supplied

Association between serum levels of reactive nitrogen intermediates and coma in children with cerebral malaria in Papua New Guinea.

Serum levels of reactive nitrogen intermediates (RNI; nitrate plus nitrite) were measured in 92 patients with cerebral malaria in the Madang Province of Papua New Guinea. RNI levels were compared to disease severity and clinical outcome, and correlated with both the depth of coma on admission and its duration. Median levels were higher among children with deeper coma than among those with lighter coma (35.6 microM vs. 16.7 microM; P = 0.008) and also among children with longer duration of coma (72 h; 59.3 microM vs. 19.3 microM; P = 0.004). RNI levels also correlated with clinical outcome, fatal cases having significantly higher RNI levels than survivors (41.2 microM vs. 18.5 microM; P = 0.014). Thus, high RNI levels are associated with indices of disease severity and may predict outcome in children with cerebral malaria. These data are consistent with the hypothesis that nitric oxide is involved in the pathogenesis of coma in human cerebral malaria.

Child↗
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Serum creatinine levels and reactive nitrogen intermediates in children with cerebral malaria in Papua New Guinea.

Serum from 41 of 92 children admitted to Madang Hospital, Papua New Guinea, with cerebral malaria, previously assessed for serum levels of reactive nitrogen intermediates (RNI: nitrate plus nitrite), were re-assessed for creatinine levels on the day of admission. Further analysis of RNI levels on day 21 compared to day 0 was carried out. Children with the highest RNI levels on admission, and with the longest duration of coma, did not have elevated creatinine levels. The highest levels of creatinine occurred among those with the lightest coma and creatinine levels were similar in those with short (< 48 h) and long (> 48 h) duration of coma. Between days 0 and 21, RNI decreased in 30 of 57 children, increased in 23, and did not change in 4. There was a significant relationship between the decrease in RNI relative to the level of RNI on admission and the duration of coma. For children with a coma duration < 48 h (48/57), there was no difference between the numbers showing an increase or a decrease in RNI level, but 6 of the 9 children with coma duration > 48 h showed a decrease in RNI greater than 50% of the RNI levels on admission. None of these 9 children had elevated creatinine levels. Elevated RNI levels in severe cases were thus not associated with renal function in these children in Papua New Guinea.

Biomarkers↗
PubMedDate not supplied

The ratio of reactive nitrogen intermediates to tumour necrosis factor and clinical outcome of falciparum malaria disease.

Serum levels of reactive nitrogen intermediates (RNI; nitrate + nitrite), interferon gamma (IFN gamma) and tumour necrosis factor (TNF) were measured in 177 Papua New Guinean children with different clinical manifestations of malaria. The groups investigated were asymptomatic parasitaemic, mild malaria, cerebral malaria survivors and cerebral malaria non-survivors. The levels of TNF were highest among the cases of cerebral malaria who died and lowest among the asymptomatic parasitaemic children (mean log TNF levels 2.183 pg/mL vs. 1.455 pg/mL; P = 0.001). Similarly, the levels of IFN gamma were highest among the cerebral and lowest among the asymptomatic patients (mean log TNF levels 0.338 pg/mL vs 0.054 pg/mL; P < 0.0001). RNI levels were high among both the asymptomatic parasitaemic group and those who died due to cerebral malaria (mean log RNI levels 1.56 microM vs. 1.412 microM; P = 0.18). The ratio of RNI to TNF, however, was significantly higher among the asymptomatic parasitaemic children and lowest among those who died due to cerebral malaria (mean log (RNI:TNF) ratio 0.118 vs. -0.789; P < 0.001). We concluded that the ratio of serum RNI to serum TNF is a more useful indicator of outcome of falciparum malaria in this population than the absolute levels of either alone.

Biomarkers↗