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Biomedical subjects

S L James

Publications and source records attributed to S L James.

At least 37 records · Page 2Linked to original sources
PubMed1995

Vaccination routes that fail to elicit protective immunity against Schistosoma mansoni induce the production of TGF-beta, which down-regulates macrophage antiparasitic activity.

C57BL/6 mice immunized intradermally (i.d.) with bacillus Calmette Guerin (BCG) plus killed skin-stage schistosomula are protected against subsequent infection with Schistosoma mansoni, whereas immunization by i.v. or i.m. routes is not protective. Moreover, previous immunization via the nonprotective i.v. route interfered with the ability to subsequently induce protection by i.d. vaccination, suggesting that inhibitory responses are invoked. Given the evidence that activated macrophages (M phi) play a role as effector cells in protection against schistosomiasis, we investigated the ability of spleen cells from protected and nonprotected immunized mice to produce M phi activating and deactivating cytokines. Exposure to supernatant fluids (SNs) from Ag stimulated spleen cells of i.d., but not i.v. or i.m., immunized mice activated inflammatory M phi for in vitro killing of schistosome larvae, through a mechanism dependent on both IFN gamma and TNF-alpha. No evidence was observed for the preferential induction of the M phi activating Th1 cytokines IFN-gamma and IL-2 in i.d. immunized mice, nor did spleen cells from nonprotected animals produce higher levels of the Th2 associated cytokines IL-4 and IL-10, which are known to prevent M phi activation. TGF-beta was, however, detected in SNs from unprotected mice. Moreover, the M phi inhibitory activity detected in these SNs was heat stable and neutralized by anti-TGF-beta Abs, suggesting that production of TGF-beta is at least partially responsible for the failure of i.m. and i.v. immunized mice to develop immunity to S. mansoni. Thus, the induction of down-regulatory cytokines may be an important factor limiting the efficacy of certain vaccination protocols.

Animals↗
PubMed1995

Psychological outcome of ECMO-eligible neonates with severe respiratory failure treated using conventional medical therapy.

OBJECTIVE: The present study addressed a National Health and Medical Research Council (NHMRC) recommendation that the outcome of neonates who are treated conventionally for respiratory problems be further investigated before setting up additional extracorporeal membrane oxygenation (ECMO) centres in Australia. METHODOLOGY: The cognitive and behavioural outcome of ECMO eligible infants who received conventional treatment for respiratory problems at birth was assessed in 18 infants aged 1.5-3 years (index group). ECMO was not available at either of the treating hospitals. Index children were compared to a matched control group of children who did not experience any major complications at birth. Children were assessed using either the Bayley or McCarthy scales of infant development and the Child Behavior Checklist. RESULTS: Overall, a mortality rate of 19% and a psychological morbidity rate of 18% suggest that children born with severe respiratory failure, who meet existing ECMO eligibility criteria, have a good prognosis when treated using conventional medical therapy. CONCLUSIONS: Improvements to conventional treatments indicate that ECMO eligibility criteria may need to be revised to identify accurately those infants who are at extreme risk of mortality if treated conventionally.

Adaptation, Psychological↗
PubMed1995

Role of nitric oxide in parasitic infections.

Nitric oxide is produced by a number of different cell types in response to cytokine stimulation and thus has been found to play a role in immunologically mediated protection against a growing list of protozoan and helminth parasites in vitro and in animal models. The biochemical basis of its effects on the parasite targets appears to involve primarily inactivation of enzymes crucial to energy metabolism and growth, although it has other biologic activities as well. NO is produced not only by macrophages and macrophage-like cells commonly associated with the effector arm of cell-mediated immune reactivity but also by cells commonly considered to lie outside the immunologic network, such as hepatocytes and endothelial cells, which are intimately involved in the life cycle of a number of parasites. NO production is stimulated by gamma interferon in combination with tumor necrosis factor alpha or other secondary activation signals and is regulated by a number of cytokines (especially interleukin-4, interleukin-10, and transforming growth factor beta) and other mediators, as well as through its own inherent inhibitory activity. The potential for design of prevention and/or intervention approaches against parasitic infection (e.g., vaccination or combination chemo- and immunotherapy strategies) on the basis of induction of cell-mediated immunity and NO production appears to be great, but the possible pathogenic consequences of overproduction of NO must be taken into account. Moreover, more research on the role and regulation of NO in human parasitic infection is needed before its possible clinical relevance can be determined.

Animals↗
PubMed1995

Nebulised amiloride in respiratory exacerbations of cystic fibrosis: a randomised controlled trial.

OBJECTIVE: To assess the benefit of nebulised amiloride added to the standard inpatient treatment of a respiratory exacerbation in cystic fibrosis. DESIGN: Prospective, randomised, double blind, placebo controlled trial. SUBJECTS: 27 cystic fibrosis patients (mean age 12.8 years). SETTING: Two hospitals in Leeds, UK. RESULTS: Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) showed improvements over the course of treatment, although there was no difference in respiratory function between the two groups at any of three time periods during the study. The time to reach peak FVC was significantly reduced in the amiloride group (4.2 v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time to reach peak FEV1 (5.7 v 7.9 days; 95% CI -1.2 to 5.6 days). CONCLUSIONS: Amiloride did not result in a greater overall improvement in respiratory function. There was a suggestion that it may have an effect on the rate of improvement, and thus may possibly influence the duration of treatment. This hypothesis deserves further evaluation.

Adolescent↗
PubMed1995

Surface modification of albumin microspheres.

Submicron sized hydrophobic and hydrophilic albumin microspheres (MS) were prepared using a chemical crosslinking technique. Spermine was linked to the surface of the hydrophilic MS. The degree of hydrophobicity for these three types of MS was investigated using a novel technique of sedimentation volume. The surface tension of the hydrophobic MS was 31 mN m-1. The ST of the hydrophilic MS was 68 mN m-1, whereas the surface tension of spermine-linked MS corresponded to 62, 65.5, 69 and 71 mN m-1 indicating heterogeneous hydrophilic characteristics. Ligands can be successfully linked to MS using a water-soluble carbodiimide.

Albumins↗
PubMed1995

Proximal tibial derotation osteotomy for anterior knee pain in the miserably malaligned extremity.

In an 18-year review period, 10 patients were identified with debilitating anterior knee pain and severe rotational malalignment of the lower extremity. Eight of the most symptomatic knees in 7 of these patients were treated with a rotational osteotomy of the tibia performed proximal to the tibial tubercle. Six of the 7 patients who fit a previously described spectrum of rotational deformity consisting of mild femoral anteversion, severe external tibial torsion, mild tibia vara, and pes planovalgus deformity, underwent unilateral procedures for external tibial torsion. Duration of preoperative symptoms averaged 6.3 years. Intraoperative torsional correction obtained with internal rotation of the tibia averaged 19.7 degrees. Subjectively, 1 excellent, 5 good, and 1 fair result were obtained. Functionally, 3 excellent and 4 good results were obtained. Follow-up evaluation averaging 10 years revealed no deterioration of the results, proving the success of the procedure in this group of select individuals over the long term.

Bone Malalignment↗
PubMed1994

Elevated expression of Th1 cytokines and nitric oxide synthase in the lungs of vaccinated mice after challenge infection with Schistosoma mansoni.

C57BL/6 mice were vaccinated with irradiated cercariae of Schistosoma mansoni, and, at various times after challenge infection, total lung mRNA was isolated to assess the induction of several cytokines that previously had been shown in in vitro studies to be involved in the activation of macrophages and/or endothelial cells for nitric oxide (NO) production and killing of schistosomula. Vaccinated mice demonstrated a highly significant increase in IFN-gamma mRNA upon subsequent infection when compared with infected nonvaccinated controls. A similar, although less dramatic, increase in two other macrophage-activating cytokines, TNF-alpha and IL-2, also was observed. In contrast, although the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 were elevated in challenged vaccinated animals, only IL-10 and IL-13 showed increases that were significant with respect to the mRNA levels observed in challenged controls. Neutralization of IFN-gamma reduced immunity in vaccinated animals and resulted in decreased IFN-gamma, IL-2, IL-10, TNF-alpha, and IL-12 p40 but markedly increased IL-4, IL-5, and IL-13 mRNA expression and serum IgE levels. Pulmonary NO synthase expression was elevated in immunized mice at a time at which immune elimination of schistosomula is believed to occur. Moreover, suppression of NO synthase activity with the inhibitor aminoguanidine reduced immunity, as measured by a 32 to 33% increase in worm burden. Together, these data support previous in vitro studies that suggest a role for NO in schistosomulum killing. Furthermore, the observation that the down-regulatory cytokines IL-4, IL-10, and IL-13 are induced together with IFN-gamma may provide an explanation for the failure of this vaccine to provide complete protection.

Amino Acid Oxidoreductases↗
PubMed1994

Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide.

Like many pathogens that undergo an intravascular stage of development, larvae of the helminth parasite Schistosoma mansoni migrate through the blood vessels, where they are in close contact with endothelial cells. In vitro exposure of murine endothelial cells to various cytokines (interferon gamma, tumor necrosis factor alpha, and interleukin 1 alpha or 1 beta) resulted in their activation to kill schistosomula through an arginine-dependent mechanism involving production of nitric oxide (NO). Cytokine-treated endothelial cells showed increased expression of mRNA for the inducible form of the NO synthase, and both NO production and larval killing were suppressed by treatment with competitive inhibitors. The effector function of cytokine-treated endothelial cells was similar to that of activated inflammatory tissue macrophages, although activation appeared to be differentially regulated in these two cell types. Activated endothelial cells killed older (18-day) forms of the parasite, such as those currently thought to be a primary target of immune elimination in the lungs of mice previously vaccinated with radiation-attenuated cercariae, as well as newly transformed larvae. In C57BL/6 mice, which become resistant to S. mansoni infection as a result of vaccination with irradiated cercariae, endothelial cell morphology characteristic of activation was observed in the lung by 1-2 weeks after challenge infection. Similar endothelial cell changes were absent in P-strain mice, which do not become resistant as a result of vaccination. Together, these observations indicate that endothelial cells, not traditionally considered to be part of the immune system, may play an important role in immunity to S. mansoni and, by means of NO-dependent killing, could serve as effectors of resistance to other intravascular pathogens.

Amino Acid Oxidoreductases↗
PubMed1994

NO as an effector molecule of parasite killing: modulation of its synthesis by cytokines.

It has recently been appreciated that NO, a molecule previously known to play a physiologic role in blood pressure regulation, is a major effector molecule of macrophage cytotoxicity against a variety of microbial targets, including protozoan and helminth parasites. NO production by macrophages is arginine dependent and catalyzed by a cytokine-inducible form of the NO synthase. This activity is positively controlled by several up-regulatory stimuli (including IFN-gamma, TNF-alpha, IL-2) and negatively controlled by others (principally IL-10, IL-4, TGF-beta). Other cell types, such as endothelial cells and hepatocytes, display a similar capacity for NO production in response to cytokine stimulation. In murine models of leishmaniasis and schistosomiasis, in vivo NO synthesis correlates with protective immunity against infection. The effector molecule that plays a similar role in cell-mediated immunity in man has not yet been identified.

Amino Acid Oxidoreductases↗
PubMed1994

Alcoholism in homeless veterans: a historical overview.

The department of Veterans Affairs uses a variety of approaches to assist homeless veterans suffering from alcoholism, including outreach and domiciliary programs. The history of alcoholism and homelessness is discussed in this article and characteristics of homeless veterans are delineated. Cultural considerations, treatment options, and the role of the CNS working with this population are presented. Implications for further research are included.

Alcoholism↗
PubMed1994

Drug discovery, development and deployment: a report from the 28th Joint Conference of the U.S.-Japan Parasitic Diseases Panels, Baltimore, Maryland, July 1993.

The 28th Joint Conference of the Parasitic Diseases Panels of the U.S.-Japan Cooperative Medical Sciences Program held in Baltimore, Maryland focused on current research within both countries on antiparasitic chemotherapy. This meeting report summarizes presentations of work in progress on antiparasitic drugs currently in use and drugs under development or in clinical trials, as well as reports on potentially unique parasite characteristics that may provide targets for development of future therapeutics.

Animals↗
PubMed1993

Effector functions of activated macrophages against parasites.

Evidence in experimental animals indicates a major role for cytokine-activated macrophages as effector cells in protective immunity against parasites. Research on cytokine function during this past year has contributed many insights into the immune mechanisms regulating murine macrophage function as well as the effector molecules employed by these cells to kill both intracellular and extracellular parasites.

Animals↗
PubMed1992

Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation.

Interleukin 10 (IL-10) inhibits interferon gamma-induced macrophage activation for cytotoxicity against larvae of the human parasite Schistosoma mansoni by suppressing production of the toxic effector molecule nitric oxide (NO). In this study, the mechanism of IL-10 action was identified as inhibition of endogenous tumor necrosis factor alpha (TNF-alpha) production by interferon gamma-activated macrophages. TNF-alpha appears to serve as a cofactor for interferon gamma-mediated activation, since both schistosomulum killing and NO production were inhibited by anti-TNF-alpha antibody, whereas TNF-alpha alone was unable to stimulate these macrophage functions. IL-10 blocked TNF-alpha production by interferon gamma-treated macrophages at the levels of both protein and mRNA synthesis. Addition of exogenous TNF-alpha reversed IL-10-mediated suppression of macrophage cytotoxic activity as well as NO production. Likewise, addition of a macrophage-triggering agent (bacterial lipopolysaccharide or muramyl dipeptide), which induced the production of TNF-alpha, also reversed the suppressive effect of IL-10 on cytotoxic function. In contrast to IL-10, two other cytokines, IL-4 and transforming growth factor beta, which also inhibit macrophage activation for schistosomulum killing and NO production, did not substantially suppress endogenous TNF-alpha production. These results, therefore, describe a separate pathway by which macrophage microbicidal function is inhibited by the down-regulatory cytokine IL-10.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity.

After activation with IFN-gamma, thioglycollate-elicited murine peritoneal macrophages kill schistosomula of Schistosoma mansoni in vitro by an L-arginine-dependent mechanism which involves the production of reactive nitrogen oxides (NO). In the present study we demonstrate that the regulatory cytokines IL-10, IL-4, and transforming growth factor-beta (TGF-beta) are potent inhibitors of this extracellular killing function of activated macrophages. Each cytokine was found to suppress killing of schistosomula in a dose-dependent fashion. The activity of IL-10 was not permanent, because subsequent treatment with additional IFN-gamma 2 to 6 h later reversed the inhibition of macrophage larval killing. More importantly, the combination of suboptimal levels of any two of these three cytokines was found to give a potent synergistic suppression of schistosomulum killing by IFN-gamma-treated macrophages. Similarly, IL-10, IL-4, or TGF-beta alone blocked the production of NO, and when used in combination these cytokines exhibited an enhanced inhibitory effect on nitrite production. Macrophage-mediated killing of schistosomula through the generation of NO has been shown previously to be a major effector mechanism of schistosome immunity. The results presented here suggest that the suppression of this mechanism by induction of the regulatory cytokines IL-10, IL-4, and TGF-beta, which are known to be produced during schistosome infection, may be an important strategy used by the parasite to evade macrophage-mediated immune destruction.

Animals↗