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L Schofield

Publications and source records attributed to L Schofield.

44 records · Page 3Linked to original sources
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Immediate post-dosing paralysis following severe soman and VX toxicosis in guinea pigs.

There have been numerous studies of the central nervous system (CNS) involvement in organophosphate (OP) poisoning showing status epilepticus and/or 'electrographic seizures'. Brain damage has been demonstrated as 'neuronal necrosis' primarily in the cortex, thalamus and hippocampus. To the authors' knowledge there have been no reports of partial/total paralysis following close upon OP exposure although delayed paralysis has been reported. This report summarizes the immediate, OP induced paralytic events recorded in guinea pigs during development of the Canadian reactive skin decontaminant lotion (RSDL). As part of the development work, supra-lethal cutaneous doses of OP were applied to large numbers of guinea pigs followed by decontamination with the RSDL or predecessor lotions and solvents. Soman (pinacolyl methylphosphonofluoridate; GD) challenges were applied to 1277 animals and S-(2-diisopropyl-aminoethyl) methylphosphorothiolate (VX) challenges to 108. The classic sequence of clinical signs--ptyalism, tremors, fasciculations, convulsions, apnea and flaccid paralysis before death--was seen in the 658 animals that died and in many of the survivors. Eighty-four of 688 survivors of GD and 4 of 39 survivors of VX showed random paralysis of various distal regions following recovery from an insult which produced convulsions and/or flaccid paralysis. Because the experiments were designed to assess the decontamination procedures, there were no apparent relationships between the amounts of OP applied and the sequellae recorded. The observations of paralysis were also incidental to the prime focus of the experiments. Because of this, only ten animals paralysed following GD exposure were examined for histological effects. The pathologist diagnosed 'encephalomalacia' and 'focal necrotic lesions' in the cerebral cortex and 'focal necrotic lesions' in one spinal cord. Of the 84 guinea pigs paralysed after GD challenge, one was not decontaminated and the decontaminants used on the remainder were sufficiently varied that there appeared to be no relationship between the type of decontaminant and the resulting paralysis.

Animals↗
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Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites.

This study was designed to test the hypothesis that T-cell effector mechanisms are required for protective immunity to malaria sporozoites. Administration of neutralizing monoclonal antibodies against gamma interferon (gamma IFN) to immune hosts, reversed sterile immunity to sporozoite challenge, by allowing the growth of exoerythrocytic forms (EEF) and thus the development of parasitaemia. Immune animals also developed infections when depleted in vivo of their suppressor/cytotoxic T cells expressing the CD8 antigen (CD8+) but not when depleted of helper T cells expressing CD4 antigen (CD4+), before sporozoite challenge. Passive transfer of immune immunoglobin alone, or adoptive transfer of immune T cells alone, conferred partial protection to naive recipients. Transfer of both immune components resulted in significantly greater protection. This transferred immunity was reversed by the in vivo neutralization of gamma IFN. Thus, sterile immunity to sporozoite challenge requires the neutralization of sporozoites by antibodies and the inhibition of EEF development by gamma IFN with the participation of CD8+ cells.

Animals↗
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Technetium-99m glucarate uptake in a swine model of limited flow plus increased demand.

BACKGROUND: Glucarate is a 6-carbon dicarboxylic acid shown to be taken up by necrotic myocytes, binding to nuclear histones in animal models of coronary occlusion, resulting in infarction. This study investigated glucarate uptake in a model of severe ischemia. METHODS AND RESULTS: Thirty-five experiments were performed, in which a catheter-mounted stenosis (reducing lumen dimensions by 80%) was placed in the left anterior descending coronary artery (LAD) of an anesthetized, instrumented domestic swine and technetium-99m glucarate (GLU) was injected during the last minute of 5 minutes of pacing. Hemodynamic and blood flow measurements were performed at control, during pacing, and during recovery. The animals were killed; their hearts were stained with fluorescein dye and triphenyl tetrazolium chloride (TTC). Electron micography (EM; n = 6) and cell centrifugation (n = 7) were also performed. On the basis of net lactate production and severe blood flow reduction in the risk region (RR), ischemia with pacing developed in 25 animals. Fifteen of 25 animals showed tracer uptake in the RR on in vivo and ex vivo imaging (scan positive), and 10 were scan negative in the RR. Endocardial blood flow in the RR during pacing was 0.28+/-0.16 mL/g/min for scan-positive and 0.30+/-0.17 mL/g/min for scan-negative experiments (P = not significant [NS]). Transmyocardial net lactate extraction during pacing was -63%+/-44% for scan-positive and -53%+/-60% for scan-negative experiments (P = NS). Control and recovery heart rates were higher in scan-positive experiments (108+/-14 vs. 92+/-17, and 125+/-24 vs. 104+/-18, P<.02). Lactate extraction was lower during control and recovery in scan-positive animals (2+/-29 vs. 30+/-19, P = .03). Scan-positive animals had a more proximal stenosis position. Minimal necrosis was documented by means of TTC negative staining in 8 of 15 scan-positive experiments (comprising 10%+/-4.3% of RR area). EM or cell fractionation was performed in 5 of the 7 remaining scan-positive and TTC-positive hearts, and in those 5 experiments, necrosis was documented by means of EM in 2 and by means of cell fractionation in 3. CONCLUSIONS: Uptake of Tc-99m glucarate was seen in the RR in a swine model of ischemia severe enough to produce myocyte injury and early cell death.

Animals↗
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Education, Nursing, Baccalaureate↗
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Regulating immunity to malaria.

The optimal outcome of a malaria infection is that parasitized cells are killed and degraded without inducing significant pathology. Since much of the pathology of malaria infection can be immune-mediated, this implies that immune responses have to be carefully regulated. The mechanisms by which anti-malarial immune responses are believed to be regulated were discussed at the recent Malaria Immunology Workshop (Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; February 2005). Potential regulatory mechanisms include regulatory T cells, which have been shown to significantly modify cellular immune responses to various protozoan infections, including leishmania and malaria; neutralising antibodies to pro-inflammatory malarial toxins such as glycosylphosphatidylinositol and haemozoin; and self-regulating networks of effector molecules. Innate and adaptive immune responses are further moderated by the broader immunological environment, which is influenced by both the genetic background of the host and by co-infection with other pathogens. A detailed understanding of the interplay between these different immunoregulatory processes may facilitate the rationale design of vaccines and novel therapeutics.

Animals↗
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Preconditioning myocardium with demand ischemia in the presence of a critical coronary artery stenosis.

The relative importance of adrenergic stimulation and demand ischemia as important preconditioning stimuli remains unclarified. The purpose of this investigation was to use a partial coronary stenosis to define the preconditioning role of demand ischemia. Dobutamine was infused intravenously before coronary occlusion in closed-chest swine with and without an artificial coronary stenosis in the mid-left anterior descending coronary artery. Control animals had no stenosis and did not receive dobutamine before occlusion. All three groups underwent 45 minutes of occlusion followed by 120 minutes of reperfusion. At baseline, regional myocardial blood flow in the area at risk was reduced in animals with a stenosis, but global left ventricular systolic function, measured by gated blood pool scan, was equivalent in all three groups. Animals with and without a stenosis received equivalent catecholamine stress with dobutamine, but only animals with a stenosis manifested ischemia during the infusion. At 2 hours after reperfusion, infarct size as a percentage of the area at risk was smaller in animals with a stenosis given dobutamine. Demand ischemia preconditions myocardium in closed-chest swine. Increased demand alone without ischemia had marginal preconditioning effects. This may have clinical relevance to patients with severe stenoses exposed to stressful stimuli before the development of myocardial infarction.

Adrenergic beta-Agonists↗
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Antigen-induced (Dumonde Glynn) arthritis in the sheep: a large joint animal model of arthritis.

OBJECTIVE: To determine if the Dumonde Glynn model of arthritis can be established in sheep since a larger model would facilitate injection and the measurement of joints. METHODS: Three groups of sheep were immunised with ovalbumin in Freund's adjuvant. Arthritis was induced in group 1 (n = 10, by the injection of 5 mg ovalbumin in 0.5 ml to the right hock joint. Control groups received saline (n = 10) or no treatment (n = 6). RESULTS: Following joint injection the mean AP diameter increased so that there was a 32% difference between the right and left joints at 24 hr (p < 0.001) declining gradually to 12% (p < 0.01) 19 days after the induction of arthritis. The level of haptoglobin in group 1 prior to the induction of arthritis was 0.04 +/- 0.01. Haemoglobin binding capacity (mg/ml) peaked on day 3 at 0.33 +/- 0.13 (p < 0.01), and was 0.110 +/- 0.05 thirteen days after joint injection. Features observed included proliferation of the joint lining, fibrin deposition and early erosion of cartilage. Synovial membrane showed an infiltrate of inflammatory cells identified as monocytes/macrophages and lymphocytes. Synovial histology scores were 1.8 +/- 0.2 for the left joint and 9.3 +/- 0.73 for the arthritic right joint. CONCLUSION: We conclude that this is a model of mono-arthritis particularly useful when a larger joint is required for intra-articular injection or repeated joint measurements such as in a clinical trial.

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