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Biomedical subjects

J S Cameron

Publications and source records attributed to J S Cameron.

At least 91 records · Page 5Linked to original sources
PubMed1992

In situ expression of tumor necrosis factor-alpha, interferon-gamma, and interleukin-2 receptors in renal allograft biopsies.

The production and release of cytokines and their receptors are of critical importance in mediating graft injury. In order to evaluate the expression of cytokines in renal allograft biopsies, we performed immunocytochemical studies to detect activated cells positive for TNF-alpha, IFN-gamma, and IL-2R, using an alkaline phosphatase anti-alkaline phosphatase technique (APAAP). Sixty-one biopsy specimens from renal transplant patients were analyzed and were classified according to both clinical and conventional morphological criteria. There was a significant correlation between the number of positive cells reactive with monoclonal antibodies directed against TNF-alpha, IFN-gamma, and IL-2R and the presence of acute cellular rejection. The mean number of infiltrating cells (cells/mm2) positive for TNF-alpha (9.2 +/- 1.1), IFN-gamma (6.7 +/- 1.7), and IL-2R (31.2 +/- 4.8) was significantly greater in acute cellular rejection episodes compared with nonrejecting kidneys (0.9 +/- 0.2, 1.2 +/- 0.4, and 8.8 +/- 2.9 positive cells/mm2 for TNF-alpha, IFN-gamma, and IL-2R, respectively). No significant expression of these cytokines was found in the majority of biopsies with chronic rejection. In two cases, in which acute cellular rejection was not sustained on clinical grounds but was diagnosed on histology, the expression of TNF-alpha, IFN-gamma, and IL-2R was similar to that observed in typical cellular rejection. We conclude that TNF-alpha, IFN-gamma, and IL-2R are markedly expressed by activated mononuclear infiltrating cells in acute cellular rejection, and that these cytokines play an important role in allograft rejection. The immunocytochemical evaluation of cytokine expression is a simple and rapid method that is helpful in differentiating acute cellular rejection from other causes of graft disfunction.

Adolescent↗
PubMed1992

Different mechanisms by which anti-DNA MoAbs bind to human endothelial cells and glomerular mesangial cells.

The mechanisms by which anti-DNA MoAbs derived from MRL-lpr/lpr mice, bind to human umbilical vein endothelial cells (HUVEC) and glomerular mesangial cells were studied using a cellular ELISA. DNAse-treatment of either the MoAb or HUVEC followed by reconstitution with DNA and/or histones was performed to determine whether DNA and histones mediated such binding. It was found that MoAb410 bound to HUVEC and mesangial cells in the form of preformed DNA/anti-DNA immune complex, and such binding was facilitated by histones. In contrast, MoAb 152 bound directly to cell membrane-associated DNA, and adding DNA to MoAb 152 reduced its cellular binding. DNA binds endothelial cell surface and histones enhance the binding of both MoAb 410 and MoAb 152 to HUVEC by increasing cell membrane-associated DNA. Finally, the degree of MoAb binding to HUVEC is critically influenced by the relative concentrations of antibody, DNA, and histones.

Antibodies, Antinuclear↗
PubMed1992

Membranous nephropathy and its treatment.

Membranous nephropathy is a histological appearance which indicates a particular immunopathogenesis, but may have many basic aetiologies and is probably not a single disease. It is predominantly an appearance seen in middle-aged and elderly individuals, and in general has a slow progression over years or even decades towards remission or renal impairment in almost equal proportions. An aggressive search for associated disease is worthwhile, and one should wait to see what the evolution of proteinuria and renal function may be. If a progressive course becomes evident, then a trial of treatment with corticosteroids is worthwhile, but if this is ineffective, a more aggressive approach involving the use of alkylating agents may be justified. Cyclosporin does not appear to have a major effect in the majority of patients, and intravenous gammaglobulin is under evaluation at the moment with some encouraging results. The best treatment regime remains to be determined.

Adrenal Cortex Hormones↗
PubMed1992

Effects of diazoxide and glyburide on ATP-sensitive K+ channels from hypertrophied ventricular myocytes.

Hyperpolarizing vasodilators that specifically activate ATP-sensitive K+ currents (IK(ATP] in smooth muscle have been suggested as promising antihypertensive (if potentially arrhythmogenic and/or hyperglycemic) therapy. To date, however, the effects of agents presumed to influence these channels have not been characterized in hypertrophied cardiac muscle secondary to chronic hypertension. We used standard intracellular and patch clamp, single-channel recording techniques to study the effects of diazoxide, a presumed activator, as well as the sulfonylurea glyburide on IK(ATP) in cardiac muscle from control (WKY) and spontaneously hypertensive rats (SHR). Intracellular recordings were obtained from isolated left ventricles at 37 degrees C; unitary currents were recorded in excised, inside-out membrane patches with symmetrical transmembrane K+ at 21-23 degrees C. Diazoxide (5-100 microM) caused a decrease in action potential duration in both WKY and SHR ventricles. Glyburide (5-25 microM) produced dramatic dose-dependent increases in action potential duration approaching 100% in both groups. Action potential amplitude and resting membrane potential were unaffected by either agent. Before drug administration, unitary currents in hypertrophied myocytes exhibited a greater open state probability upon depolarization than those from control myocytes, although conductance, mean single-channel open time, and the number of channels per patch were not significantly different. Under patch clamp, both diazoxide (25 and 100 microM) and glyburide (50 microM) decreased IK(ATP) activity in cells from WKY and SHR in the absence of ATP. In both groups, the response reflected an overall decrease in open state probability. These data indicate that although IK(ATP) characteristics are altered in hypertension and myocardial hypertrophy, the effects of agents specific to this current are not significantly different in cells from SHR relative to control. On the other hand, the effects of diazoxide may be linked to temperature or to the metabolic state of the cell.

Adenosine Diphosphate↗
PubMed1991

New horizons in renal vasculitis.

After a long period during which few new data on the vasculitides emerged, the past decade has seen a real explosion of data on the subject. This began with basic clinical descriptions and the delineation of long term outcome as survival improved to a major extent under the influence of improved treatment regimes. In parallel, better understanding of the immunopathology has emerged. Of particular interest have been descriptions of autoantibody systems in vasculitis which seem to be specific to vasculitis and therefore diagnostically useful: the antineutrophil cytoplasmic antibodies (ANCA). Whether or not these are pathogenetically significant as well as useful remains a matter for debate. In parallel, anti endothelial cell antibodies have been described, but their role (if any), in pathogenesis remains equally obscure. There are some suggestions that vasculitis is becoming more common, but increased awareness and the availability of ANCA have undoubtedly increased awareness of the subject.

Autoimmune Diseases↗
PubMed1991

Recurrent primary disease and de novo nephritis following renal transplantation.

Recurrent or de novo diseases account for only 5% of graft failure in children, but have much to teach us about mechanisms. In children, almost the only metabolic disease with recurrence is type I hyperoxaluria, in which the poor long-term results of isolated renal transplantation make combined liver and renal transplantation, or even prophylactic liver transplantation before renal failure the preferable alternatives. While many forms of nephritis may show histological recurrence in allografts, it is notable that in many patients this is accompanied by no clinical manifestations or only mild disease: this is particularly so in mesangiocapillary glomerulonephritis (MCGN) type II. IgA-associated nephropathy and Henoch-Schönlein purpura. However focal segmental glomerulosclerosis and MCGN type I recur with sufficient frequency and severity to deter the use of living donors unless there is no alternative. The same is true of haemolytic-uraemic syndromes. As many as 10% of paediatric grafts may show de novo membranous nephropathy, but in the majority this is mild or not clinically evident. In contrast, the rare anti-glomerular basement membrane nephritis affecting some patients with Alport's syndrome usually results in graft failure, but occurs in only a minority of recipients with the syndrome. For all types of disease in allografts, risk factors for recurrence are poorly worked out, and attempts at treatment generally ineffective.

Amyloidosis↗
PubMed1991

A role for DNA in anti-DNA antibodies binding to endothelial cells.

Vascular injury and microvascular thrombosis are prominent features of systemic lupus erythematosus, as are circulating DNA-binding antibodies (DNAb). Experimental glomerulonephritis can be induced by anti-endothelial cell antibodies, and polyreactive DNAb might be pathogenetic by binding to endothelial cells, perhaps influencing their non-thrombogenic nature. To test this hypothesis, eight monoclonal antibodies (mAb) that bind to DNA derived from (NZB x NZW)F1 or MRL/Mp-lpr/lpr mice, were tested for their ability to bind to human umbilical vein endothelial cells (HUVEC). Binding was assessed using flow cytometry, fluorescence microscopy and cellular ELISA. Three of the eight mAb, at concentrations employed in this study, bound to HUVEC and dermal fibroblasts. Of these three mAb, one bound also to platelets. Two of the three demonstrated strong binding to (1) freshly isolated, collagenase-digested HUVEC, (2) 2nd passage HUVEC in suspension after trypsinization and, (3) 2nd passage HUVEC growing on plastic plates. To determine whether DNA itself acted as a ligand in this binding, prior treatment with DNAase was studied. Treatment of the endothelial cells with DNAase had no effect on the binding of one mAb, but DNAase treatment of this monoclonal itself resulted in a 60% reduction in binding to HUVEC, suggesting that the binding might be mediated through DNA in the form of a DNA/anti-DNA immune complex. In contrast, DNAase digestion of the endothelial cells caused a 40% reduction in the binding of the other two monoclonal antibodies. Furthermore, one of the two mAb bound 30% more to HUVEC after themselves being subjected to DNAase treatment. These two monoclonals may therefore be binding directly to HUVEC, possibly to DNA associated with the membrane. Prior DNAase digestion of dermal fibroblasts had a more profound effect on the binding of all three autoantibodies compared to HUVEC after similar treatment. Therefore, DNA can bind independently to either antibody or cell, thus supporting build up of complexes and capture of preformed complexes. Functionally, the binding of mAb to HUVEC did not influence thrombin-induced prostacyclin synthesis, in contrast to a control monoclonal anti-endothelial cell antibody EN4, which did.

Animals↗
PubMed1991

Significance of anti-phospholipid antibodies in patients with lupus nephritis.

Anti-phospholipid antibodies (APA) as markers or mediators of thrombosis in lupus could be of pathogenetic significance in nephritis, since glomerular capillary thrombi are an indicator of subsequent renal dysfunction. Isotype specific APA antibodies were measured, using cardiolipin as the antigen, in 76 patients with lupus nephritis. Twenty-nine percent of the patients had elevated IgG APA. Overall, 43% of patients showed raised levels of at least one isotype. In general, APA had specificity for anionic phospholipids. In vitro lupus anticoagulant activity was associated with all three isotypes of APA, but only the IgM isotype correlated with the biological false positive test for syphilis. APA were not associated with thromboses or neurological involvement, and only the IgA isotype correlated with thrombocytopenia. We confirmed an association between the presence of intraglomerular thrombi and serum IgG APA. However, we found no association between APA and renal histological pattern, or long-term renal function. Our data, therefore, do not support a major pathogenetic role for APA in the nephritis of lupus in treated patients.

Antibodies↗
PubMed1991

Orotidine accumulation in human erythrocytes during allopurinol therapy: association with high urinary oxypurinol-7-riboside concentrations in renal failure and in the Lesch-Nyhan syndrome.

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5'-monophosphate decarboxylase by oxypurinol-7-ribotide.

Allopurinol↗
PubMed1991

Expression of VCAM-1 in the normal and diseased kidney.

We have conducted an immunocytochemical analysis to investigate the presence of the recently described vascular cell adhesion molecule-1 (VCAM-1) in human kidney, using the anti-VCAM-1 monoclonal antibody 1.4C3. In normal control tissue VCAM-1 was present on some (but not all) parietal epithelial cells lining Bowman's capsule. Forty-nine of fifty clinical biopsy specimens were characterised by the additional presence of VCAM-1 on proximal tubular cells. This was most marked in biopsies of patients with interstitial nephritis or systemic vasculitis with crescentic nephritis, but was also observed in biopsies with minimal change, IgA or lupus nephropathy, or from patients with diabetic nephropathy, amyloid, or gout. Proximal tubule VCAM-1 correlated significantly with the number of transferrin-receptor-positive leukocytes (r = 0.607, p less than 0.0001) in the interstitium, but not with expression of HLA-DR by tubular cells. Surprisingly, VCAM-1 was not observed on vascular endothelial cells in these biopsies, even in the presence of a marked infiltrate; this contrasts with other tissues (e.g. skin and synovium). The presence of VCAM-1 on tubular cells in the inflamed kidney indicates the potential for these cells to interact with mononuclear cells, either as accessory cells or as cytotoxic targets. The unexpected absence of VCAM-1 in renal vascular endothelial cells suggests local differences in the endothelial cells of this organ.

Antibodies, Monoclonal↗