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Biomedical subjects

S L James

Publications and source records attributed to S L James.

At least 55 records · Page 3Linked to original sources
PubMed1992

IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages.

IL-10, a cytokine produced by CD4+ T lymphocytes belonging to the Th-2 subset, has previously been shown to inhibit the synthesis of IFN-gamma by both T cells and NK cells. We now demonstrate that IL-10 can also down-regulate IFN-gamma-dependent immunity by blocking the ability of that lymphokine to activate macrophages. Thus, IL-10, in a dose-dependent manner, inhibits the microbicidal activity of IFN-gamma-treated inflammatory macrophages against intracellular Toxoplasma gondii as well as the extracellular killing of schistosomula of Schistosoma mansoni. This suppression correlates with the inhibition by IL-10 of IFN-gamma-induced production of toxic nitrogen oxide metabolites, an effector mechanism previously implicated in the killing by macrophages of both parasite targets. IL-10 inhibition of nitric oxide production was shown to occur when the cytokine is given before or together with the IFN-gamma-activating stimulus, but not after its removal from the cultures and to require 12 h of contact for maximal suppressive effect on macrophage function. These results, taken together with previous findings on the down-regulation of Th1 lymphokine production by IL-10, indicate that the induction of IL-10 may be an important strategy by which parasites evade IFN-gamma-dependent, cell-mediated immune destruction.

Animals↗
PubMed1992

The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta.

The present study was carried out to determine the effector mechanism of anti-Trypanosoma cruzi activity by interferon (IFN)-gamma plus lipopolysaccharide (LPS)-treated macrophages. A macrophage cell line (IC-21) that failed to mount an appreciable oxidative burst was nevertheless found able to control T. cruzi growth after exposure to IFN-gamma alone or IFN-gamma plus LPS. Moreover, microbicidal functions of both inflammatory macrophages and IC-21 against T. cruzi was found to be inhibited in the presence of NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of L-arginine. Addition of supplemental L-arginine to the culture overcame the capacity of NGMMA to block activated macrophage anti-T. cruzi functions. The ability of NGMMA to reverse both parasite growth inhibition and killing by IFN-gamma plus LPS-activated macrophages was found to correlate with the suppression of nitrite accumulation in the culture supernatants. Together, these results implicate the L-arginine-dependent production of nitric oxide in T. cruzi killing by activated macrophages. We also tested the ability of interleukin(IL)-10 and transforming growth factor (TGF)-beta, to block regulation of T. cruzi growth in this system. Both IL-10 and TGF-beta inhibited anti-parasite function by IFN-gamma-activated macrophages, with an optimal dose of 100 units/ml and 0.5 ng/ml, respectively. Moreover, when used in combination, suboptimal doses of IL-10 and TGF-beta were found to produce a synergistic inhibitory effect in the regulation of T. cruzi growth. The ability of IL-10 and TGF-beta to suppress microbicidal function was also positively correlated with inhibition of nitrite generation in macrophage culture supernatants. These results predict an in vivo role for IL-10 and TGF-beta in promoting parasite survival in the face of the host cell-mediated immune response.

Animals↗
PubMed1992

Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection.

Parasitic infection is frequently accompanied by a downregulation in host cell-mediated immunity. Recent studies suggest that this modulation of helper T cells and effector cell function can at least in part be attributed to the action of a set of inhibitory cytokines produced by T lymphocytes as well as by a number of other cell types. The best characterized of these inhibitory lymphokines are IL-4, IL-10 and TGF-beta. Interestingly, both IL-4 and IL-10 are produced by the Th2 but not the Th1 subset of CD4+ helper cells. The former subset dominates in many situations of chronic or exacerbated parasitic infection and is thought to suppress Th1 function as a consequence of the cross-regulatory activity of these two cytokines. The latter hypothesis is supported by recent experiments demonstrating that mAb-mediated neutralization of IL-10 reverses suppressed IFN-gamma responses and/or disease susceptibility in mice with parasitic infections. In vivo neutralization of TGF-beta has also been reported to increase host resistance to parasite challenge. In addition to suppressing T-cell differentiation, function or proliferation, IL-4, IL-10 and TGF-beta each inhibit the ability of IFN-gamma to activate macrophages for killing of both intracellular and extracellular parasites. Moreover, the three cytokines are able to synergize with each other in downregulating these parasiticidal effects. Interestingly, each of the cytokines inhibits the production of reactive nitrogen oxides, an effector mechanism previously demonstrated to play a major role in parasite killing by activated macrophages. In the case of IL-10, this suppression of nitrogen oxide production appears to result from an inhibition of TNF-alpha synthesis leading to defective macrophage stimulation. While distant from parasites in their biology and phylogeny, some retroviruses also appear to induce an over-production in downregulatory cytokines which is closely associated with the onset of immunodeficiency. Thus, in an animal model involving infection of mice with LP-BM5 MuLV and in human HIV infection, Th2 (IL-10 and/or IL-4) cytokine synthesis is increased while Th1 (IFN-gamma and/or IL-2) cytokine production is suppressed. These observations suggest that cytokine-mediated cross-regulation may play a role in the pathogenesis of acquired immune deficiency disease, contributing both to the progression of retroviral infection and the increase in susceptibility to opportunistic infections and malignancy. Observations of similar cytokine cross-regulatory activities in organisms as diverse as helminths, protozoa and retroviruses predict that comparable mechanisms may operate in a wide variety of infectious diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Experimental models of immunization against schistosomes: lessons for vaccine development.

Schistosomiasis is a debilitating, and sometimes deadly, parasitic infection that afflicts hundreds of millions of people living in developing countries. One of the best hopes for control of this disease is vaccine development. Studies on experimental models of attenuated vaccines have proven that high levels of protective immunity can be achieved. In these systems, resistance has been shown to be directed against the migrating larval stages of the parasite and to have both cellular and humoral components. Several candidate vaccine immunogens have been identified on the basis of antibody reactivity. However, the level of protection induced by immunization with nonliving vaccines has at yet not approached the level observed with attenuated infection. Current challenges to vaccine development include identification of protective T cell immunogens, determination of ways to strengthen the immunogenicity of isolated parasite antigens, and development of methodologies to selectively stimulate protective, as opposed to ineffective or even detrimental, immune responses.

Animals↗
PubMed1992

Valgus osteotomy with anterior cruciate ligament laxity.

Some patients with medial joint degeneration post-medial meniscectomy also have a significant anterior cruciate ligament (ACL) instability. Ten patients were treated by a combined high tibial valgus osteotomy with ACL reconstruction. All patients had relief of instability and decreased pain, although only one returned to full activity. The operation is recommended as a salvage procedure for an ACL deficient knee with instability and medial joint degeneration.

Adult↗
PubMed1991

Aluminium absorption in infancy.

The use of aluminium-containing medications and aluminium contamination of infant formulae is common. We aimed to determine whether aluminium absorption occurs after antacid ingestion. Plasma and urinary levels of aluminium were measured before and after antacid therapy in seven infants whose mean gestational age was 36 +/- 2 weeks and postnatal age 11 +/- 5 days. Antacid therapy (400-800 mumol aluminium) was given with feeds for 2 days. Plasma aluminium levels increased and reached toxic levels (0.64 +/- 0.33 mumol/L vs 3.48 +/- 2.86 mumol/L, P = 0.029). Urinary aluminium: creatinine ratio also increased. These results demonstrate that infants absorb aluminium from antacids and raise the concern of aluminium toxicity.

Aluminum↗
PubMed1991

Delivery of vitamin A from parenteral nutrition solutions in neonates.

The delivery of Vitamin A from parenteral nutrition may be suboptimal. To investigate this sample solutions were prepared and Vitamins A and E concentrations from the solution bags and the efflux from the lines were measured over a 24 h period. The results show that mean Vitamin A levels in the solution bags declined from a range of 57-66% to 17% of expected over 24 h and at the efflux of the lines from a range of 13-29% to 4% of expected, giving a calculated delivery of 10% of expected. There is no improvement with light protection or an ethylene vinyl acetate system. Mixing the vitamin preparation in lipid showed less decline (from 92 to 70% of expected over 24 h), but the delivery was variable. When vitamins were added to a lipid-dextrose-amino acid solution, there was minimal loss from the solution bag and line with a calculated delivery of 94% of expected. The delivery of Vitamin E from all systems was constant with a mean calculated delivery of 74% of expected. It was concluded that the mixing of multivitamins in dextrose-amino acid-electrolyte solutions results in poor delivery of Vitamin A and this is improved by mixing lipid solution. This is important in preterm infants who are prone to become Vitamin A deficient.

Amino Acids↗
PubMed1991

Immunization against parasites: bridging the gap between attenuated and non-living vaccines.

While great progress has been made in the last decade in defining parasite antigens which are targets of host protective responses, only limited success has been achieved in the use of these molecules as effective vaccines. A consistent problem is the failure of the candidate immunogens to induce levels of protection comparable to those obtained with attenuated vaccines against the same organisms. One explanation is that the purified or recombinant molecules employed have not been presented in a form or route which induces the correct T cell or cytokine response necessary for protection. As summarized in this overview, optimal immunization with attenuated vaccines is associated with characteristic patterns of T cell subset and cytokine induction and in at least several examples has been shown to be altered by exogenous cytokine. We hypothesize that cytokine manipulation may offer a useful strategy for improving the action of existing nonliving vaccines. The gap in efficacy between attenuated and dead vaccines could also be bridged by the use of live recombinant vaccine vectors. We have previously reported that paramyosin admixed with BCG can induce partial protection against Schistosoma mansoni in mice. Our preliminary results in the construction and testing of a recombinant BCG vector incorporating schistosome paramyosin are described.

Animals↗
PubMed1990

Activation of human monocyte-derived macrophages to kill schistosomula of Schistosoma mansoni in vitro.

Human peripheral blood monocytes from normal donors were isolated by elutriation and differentiated by culture in the presence or absence of various immunomodulators. Cells were harvested between 0 and 24 days and tested for their ability to kill schistosomula of Schistosoma mansoni in vitro as a measure of activation. Freshly isolated monocytes showed no significant cytotoxic activity in the presence or absence of IFN-gamma or LPS. As the cells matured in vitro, there was a slight increase in their inherent toxicity against the parasite, which was greatly enhanced by pretreatment with either IFN-gamma or CSF-1. Optimal antibody-independent larvicidal activity occurred after stimulation with both IFN-gamma and CSF-1, using cells that had matured for at least 7 days in vitro. Under these conditions, killing of up to 70% of the larvae was observed. Although enhanced larvicidal activity was not found to strictly correlate with production of any of several proposed effector molecules examined, activated monocyte-derived macrophages were capable of producing significant amounts of H2O2 and TNF-alpha. These observations indicate that cytokine-activated human monocyte-derived macrophages are able to kill schistosome larvae by an antibody-independent mechanism, as has been observed using murine peritoneal macrophages. Stimulation with multiple differentiation and activation signals, as would occur in vivo, may be required for development of optimal larvicidal activity.

Animals↗
PubMed1990

The role of nitrogen oxides as effector molecules of parasite killing.

The many years of effort in the attempt to identify the effector molecules of lymphokineactivated macrophages have recently come to fruition with the discovery of immuneactive nitrogen oxide. Here, Stephanie James and John Hibbs discuss the novel mammalian biochemical pathways for the synthesis of inorganic nitrogen oxides that mediate antibody-independent killing of infectious agents as well as of tumor cells. Interaction with nitrogen oxides causes iron loss from critical target enzymes in invading organisms, resulting in metabolic failure of extracellular and even of intracellular parasites of the macrophages themselves.

Journal Article↗
PubMed1990

Tumour necrosis factor (TNF) as a mediator of macrophage helminthotoxic activity.

Lymphokine-activated macrophages are cytotoxic for larvae of the helminth parasite Schistosoma mansoni. That soluble secreted factors may mediate this cytotoxicity was suggested by the observation that culture supernatant fluids from stimulated macrophages also exhibited larvacidal activity. These fluids contain the monokine tumour necrosis factor (TNF). Several observations indicated that TNF is directly toxic to schistosome larvae. Cytotoxic sera taken from BCG- or S. mansoni-immunized mice after endotoxin challenge killed schistosomula in vitro, and upon gel filtration the larvacidal factor(s) in the sera co-eluted with the tumoricidal activity defined as TNF. Recombinant-derived TNF exhibited direct toxicity to schistosomula at high concentrations, or at lower concentrations in the presence of IFN gamma. The larvacidal activity of macrophage supernatant fluids was abrogated by addition of either anti-TNF antisera or Zn+2, which has been shown to inhibit TNF-induced damage of tumour cells. Anti-TNF and Zn+2 likewise suppressed schistosomulum killing by lymphokine-activated peritoneal macrophages or the IC-21 macrophage line, indicating that TNF also plays a role in the effector mechanism of larval killing by whole cells.

Animals↗
PubMed1990

Aluminum concentrations in infant formulae.

The aluminum concentrations in breast milk and in 25 commercially available infant formulae were measured. The mean concentration in breast milk was 49 micrograms/L while concentrations in most of the humanized formulae were less than 500 micrograms/L. Higher concentrations were found in Nan, Prem Enfamil and the three soya formulae. We suggest that all formulae have the potential to be contaminated with aluminium, and to varying degrees in different batches. Until it is known whether aluminium toxicity occurs in normal infants fed these formulae, it seems reasonable to expect manufacturers to routinely measure aluminium and keep aluminium contamination to a minimum. This may be especially important for formula fed to infants with compromised gastrointestinal and renal systems.

Aluminum↗
PubMed1990

The role of mucous glycoproteins in the rheologic properties of cystic fibrosis sputum.

Cystic fibrosis (CF) is characterized by excessive amounts of thick and tenacious mucous secretions that obstruct organ ducts and passages. In the respiratory tract this is associated with chronic infection resulting in the hypersecretion of purulent sputum, which the patient finds difficult to clear. We have studied the rheologic properties of purulent sputum from six patients with CF and five patients with chronic bronchitis to assess whether CF is associated with increased sputum viscoelasticity. In addition, we have isolated the major rheologic determinants, mucous glycoproteins, from CF and chronic bronchitis sputa and, using a magnetic microrheometer, investigated the possibility that the altered properties of mucus in CF are associated with abnormalities in these glycoproteins. Creep compliance analysis indicated that the CF sputa possessed raised levels of both elasticity (p less than 0.01) and viscosity (p less than 0.01). These increases in both rheologic parameters were found to be associated with increases in the DNA content (p less than 0.01) and dry weight (p less than 0.05). Mucous glycoproteins were isolated from CF and chronic bronchitis sputum samples by gel filtration on Sepharose CL4B, followed by concentration to form 8% wt/wt gels. In the absence of other sputum components, no abnormality in the rheologic properties of CF mucin gels could be detected. However, when DNA was added, the CF gels responded with increases in both elasticity and viscosity of as much as 30% (p less than 0.05), an effect not observed in the chronic bronchitis gels. These results suggest that a subtle abnormality may exist in CF mucous glycoproteins and that this could have a role in the altered physical properties of mucous secretions in CF.

Bronchitis↗
PubMed1990

The origin of DNA associated with mucus glycoproteins in cystic fibrosis sputum.

The relative importance of host and bacteria-derived deoxyribonucleic acid (DNA) in the increased viscoelasticity of purulent sputum in cystic fibrosis (CF) and other airway diseases is unclear. We report the identification of the DNA associated with mucus glycoproteins purified from the purulent sputum of 9 patients with CF. Mucus glycoproteins were purified from CF sputum by gel exclusion chromatography and the co-purifying DNA isolated by phenol extraction. Electrophoresis indicated that the DNA preparations had a size of approximately 300 to greater than 50,000 bases. The origin of the DNA was determined by slot blotting and subsequent hybridization with 32P-labelled DNA probes specific for human DNA sequences and those from bacterial species commonly isolated from CF sputum. The results indicated that in all cases the DNA was almost entirely human in origin. This implies that it is the patient's own DNA which may contribute to the rheological abnormalities of CF sputum.

Adolescent↗
PubMed1989

Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates.

Lymphokine (LK)-activated macrophages are cytotoxic for multicellular larvae of the helminth parasite Schistosoma mansoni. Macrophage-mediated larval killing was found to be arginine dependent, as indicated by inhibition in the presence of exogenous arginase or the competitive inhibitor NG-monomethyl-L-arginine. Culture supernatant fluids from the larvicidal LK-activated macrophages contained nitrite, a product of activated macrophages derived by oxidation of arginine and implicated in the antitumor and antimicrobial effector function of these cells. Nitrite was not detectable in supernatant fluids obtained from nonactivated macrophages or from macrophages stimulated with LK in the presence of arginase or NG-monomethyl-L-arginine. Addition of excess iron or the reductant sodium dithionite to LK-activated macrophage cultures also inhibited larval killing in vitro, under conditions that have been shown by others to stabilize the activity of iron-containing enzymes involved in respiration. Nitrite production was not decreased under these conditions. These observations are consistent with the hypothesis that macrophage-mediated schistosomulum killing is caused, at least in part, by a mechanism proposed for tumor cytotoxicity, whereby production of reactive nitrogen intermediates triggers iron loss from critical target cell enzymes leading to lethal metabolic inhibition. In accordance, schistosomula were shown to be killed by inhibitors of mitochondrial respiration.

Animals↗
PubMed1989

The cost of intensive and special care of the newborn.

The cost of providing intensive (level-3) and special (level-2) care for newborn infants in a tertiary perinatal service was determined prospectively and was expressed in 1984 Australian dollars. Direct costs that were expressed per occupied bed-day were $690 for level-3, high-dependency care; $421 for level-3, low-dependency care; $544 for over-all level-3 care; $242 for level-2, high-dependency care; $170 for level-2, low-dependency care; and $201 for over-all level-2 care. Each level of care generated additional costs of $42 per occupied bed-day. Taking these additional costs into account, the over-all occupied bed-day cost of level-3 and level-2 neonatal care was $339. The major components of this over-all cost were: nursing staff members, 50%; medical staff members, 11%; consumable and recyclable items, 12%; and diagnostic services, 8%.

Australia↗