Biomedical subjects

Nicholas H Hunt

Publications and source records attributed to Nicholas H Hunt.

24 records · Page 2Linked to original sources

PubMed2003

Probucol promotes functional reendothelialization in balloon-injured rabbit aortas.

BACKGROUND: Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis. METHODS AND RESULTS: Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10+/-0.08 versus P, 0.70+/-0.10; normal: C, 0.89+/-0.02 versus P, 0.83+/-0.05; P<0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, P<0.05) and in those on normal chow (37% increase, P<0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening. CONCLUSIONS: Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.

Angioplasty, Balloon↗

PubMed2003

Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria.

Cerebral malaria (CM) is a major life-threatening complication of Plasmodium falciparum infection. The nature of the pathogenetic processes leading to the cerebral complications is poorly understood. Mouse models of this condition have provided insight into the key events in pathogenesis, including those that occur before clinical symptoms are seen. Some T helper 1 (Th1) cytokines (e.g. interferon-gamma, lymphotoxin and tumour necrosis factor) have been implicated in driving the immunopathological process leading to CM, whereas some Th2 cytokines (e.g. interleukin-10, transforming growth factor-beta) appear to oppose this process. Upregulation of leukocyte adhesion molecules on the cerebral microvascular endothelium appears to be an important component of the proinflammatory actions of the cytokines. Activation of platelets in the cerebral microcirculation could also be a key event in CM. Furthermore, recent evidence has emerged indicating that cytokines might influence biochemical pathways in the brain that, in turn, could determine the outcome of CM.

Animals↗

PubMed2002

The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malaria.

A retrospective study of 261 Vietnamese adults with severe malaria was conducted to determine the relationship between cerebrospinal fluid (CSF) levels of metabolites of the kynurenine pathway, the incidence of neurologic complications, and the disease outcome. Three metabolites were measured: the excitotoxin quinolinic acid (QA); the protective receptor antagonist kynurenic acid (KA); and the proinflammatory mediator picolinic acid (PA). These measurements were related prospectively to CSF lactate levels. QA and PA levels were elevated, compared with those of controls. There was no difference in the levels of KA between these groups. Although >40% of malaria patients had QA CSF concentrations in the micromolar range, there was no association with convulsions or depth of coma. Levels of QA and PA were associated significantly with death, but a multivariate analysis suggested that these elevations were a consequence of impaired renal function. CSF lactate remained an independent and significant predictor of poor outcome.

Adolescent↗

PubMed2002

Differential effects of the antioxidant alpha-lipoic acid on the proliferation of mitogen-stimulated peripheral blood lymphocytes and leukaemic T cells.

The effects of the antioxidant alpha-lipoic acid (LA) on the proliferation of mitogen-stimulated human peripheral blood lymphocytes (HPBL) were investigated in comparison to its effects on the proliferation of two leukaemic T cell lines, Jurkat and CCRF-CEM. At low mM concentrations, LA inhibited in a dose-dependent manner DNA synthesis of HPBL stimulated with either phorbol myristate acetate (PMA) in combination with ionomycin (IoM), or phytohaemagglutinin (PHA). At similar concentrations, LA inhibited the proliferation of Jurkat and CCRF-CEM cells. However, LA was preferentially cytotoxic to the leukaemic cell lines. The selective toxicity of LA to Jurkat cells was shown by electron microscopy (EM) to be due to the induction of apoptosis. Furthermore, LA had different effects on the secretion of interleukin-2 (IL-2) and steady-state levels of IL-2 mRNA in mitogen-stimulated HPBL depending on the mitogens used. LA dramatically increased the induction of IL-2 mRNA and IL-2 protein secretion in PMA/IoM-stimulated HPBL, whereas it inhibited these in HPBL stimulated with PHA. The differential effects of LA on normal and leukaemic T lymphocytes may indicate a new route towards development of therapeutic agents.

Antioxidants↗

PubMed2002

Isolating vessels from the mouse brain for gene expression analysis using laser capture microdissection.

Studies of gene expression often examine a pool of RNA extracted from the diverse cell types making up a tissue. We have developed a method for isolating vessels from the brain in order to understand the changes occurring in the vessels during the pathogenesis of cerebral malaria. Vessels were visualised by incubating sections of mouse brain with a substrate for alkaline phosphatase. Vessels were collected by laser capture microdissection and the specificity was monitored by measuring the expression of cell-specific markers. RNA from the captured vessels was highly enriched in mRNA for genes associated with endothelial cells and pericytes. Measurement of indoleamine 2,3-dioxygenase mRNA indicated it was possible to detect changes in gene expression, due to malaria infection, occurring specifically within the vessels. Laser capture microdissection can be used to study changes in gene expression occurring at the blood-brain barrier.

Alkaline Phosphatase↗

PubMedDate not supplied

The microcirculation in severe malaria.

Severe malaria in humans and animals is initiated by interactions between malaria-infected cells, host blood cells (including monocytes, T cells and platelets) and endothelial cells of the microcirculation. Adhesion to vascular cells, and possible vascular obstruction in severe human disease, involves interaction between host receptors and parasite-derived proteins, such as the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Our understanding of how different PfEMP1 variants may target infected erythrocytes to specific sites, such as the placenta, is rapidly increasing. However, in most instances downstream immune-mediated inflammatory processes appear more central than parasite accumulation to development of severe malaria. Using genetically-manipulated animal models of severe malaria, key roles for CD8 T cells and mediators such as lymphotoxin in the pathogenesis of murine disease have been established. Experimental and human studies suggest vascular deposition of activated platelets may have a central role. Here, we review some recent advances in the understanding of severe malaria pathogenesis from human and animal studies, focusing on events at the level of the microcirculation, and highlight the role for activated host cells in initiating the pathology of the disease.

Animals↗