Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options.
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The cause of anorexia associated with neoplasia is unknown, and some investigators have suggested a central mechanism. Recent neurophysiologic studies have revealed the possible role of serotoninergic system involving tryptophan (TRP) and its indole neurotransmitter metabolites in regulating particular aspects of feeding behavior. We therefore studied plasma and brain factors affecting TRP transport through the blood-brain barrier (plasma free and total TRP, albumin, nonesterified fatty acids, plasma neutral amino acids, brain uptake index [BUI] for TRP) and central serotonin metabolism (5-HT, 5-HIAA) in young, anorexic rats bearing the Walker-256 tumor injected intramuscularly. Plasma free TRP, but not plasma total TRP, and, more important, brain TRP and brain 5-HIAA were significantly higher in tumor-bearing rats than in pair-fed control animals. The results suggest an association between altered brain TRP metabolism and feeding behavior in tumor-related anorexia.
OBJECTIVE: To compare vitamin B6 levels in rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: We measured levels of vitamin B6 in 23 adults with well-controlled RA, and in 23 healthy control subjects matched for age, sex, race, and weight. RESULTS: Although plasma folate and vitamin B12 concentrations and erythrocyte B6 activity coefficients were similar in the patients and controls, plasma levels of pyridoxal-5'-phosphate (PLP) were lower in the RA patient group (mean +/- SD 46.1 +/- 48.1 versus 69.3 +/- 58.4 nmoles/liter; P < 0.004). In multivariate analyses, PLP was inversely associated with tumor necrosis factor alpha (TNF alpha) production by peripheral blood mononuclear cells (PBMC) (P < 0.001), after adjustment for age, pain score, erythrocyte sedimentation rate, and use of nonsteroidal antiinflammatory drugs. CONCLUSION: PLP levels are reduced in patients with RA. This reduction is associated with TNF alpha production by PBMC.
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The pleiotropic cytokine tumour necrosis factor-alpha (TNF) is thought to play a central role in infectious, inflammatory and autoimmune diseases. Critical to the understanding and management of TNF-associated pathology is the development of highly specific agents capable of modifying TNF activity. We evaluated the ability of a high affinity mouse/human chimeric anti-TNF monoclonal antibody (cA2) to neutralize the in vitro and in vivo biological effects of TNF. cA2 inhibited TNF-induced mitogenesis and IL-6 secretion by human fibroblasts, TNF-priming of human neutrophils, and the stimulation of human umbilical vein endothelial cells by TNF as measured by the expression of E-selectin, ICAM-1 and procoagulant activity. cA2 also specifically blocked TNF-induced adherence of human neutrophils to an endothelial cell monolayer. Receptor binding studies suggested that neutralization resulted from cA2 blocking of TNF binding to both p55 and p75 TNF receptors on the cells. In vivo, repeated administration of cA2 to transgenic mice that constitutively express human TNF reversed the cachectic phenotype and prevented subsequent mortality. These results demonstrated that cA2 effectively neutralized a broad range of TNF biological activities both in vitro and in vivo.
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Rats (weight 150-200 g) bearing Walker-carcinoma showed tumour size dependent hypoglycemia, diminished mobilization of glycogen following glucagon stimulation and elevated values of the enzyme activity of glucose-6-(P)-ase. A further hormonal stimulation of this enzyme activity towards the values observed in normal rats after betamethasone stimulation was not possible. The values of the enzyme fructose-1,6-di-(P)-ase in liver of tumour bearing rats equalled those found in normal controls and did not show any rise after application of betamethasone. The serum levels of free fatty acids did not show any difference between normal controls and tumour bearing rats, and displayed an equal rise after intensive stimulation of peripheral lipolysis.
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The nutritional status of 11 patients with severe mitral valve disease was investigated pre-operatively and 3 months post-operatively. It was shown that they were malnourished pre-operatively, and that this appeared to be related mainly to anorexia.
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