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Biomedical subjects

S Shaldon

Publications and source records attributed to S Shaldon.

At least 19 recordsLinked to original sources
PubMed2004

Effect of advanced glycation end products on endotoxin-induced TNF-alpha, IL-1beta and IL-8 in human peripheral blood mononuclear cells.

BACKGROUND/AIMS: Advanced glycated end products (AGE) are endogenous proteins that have formed covalent complexes with sugars by a nonenzymatic process. Being proinflammatory molecules, AGE are thought to contribute to chronic systemic and local inflammatory processes associated with pathological changes in various diseases. In patients with end-stage renal disease, AGE are believed to play a role in the progression of atherosclerosis and worsening of renal failure. In patients receiving hemodialysis, AGE are thought to contribute to the inflammatory components of the therapy, particularly in diabetic patients. METHODS: In the present study, AGE were produced using 5% human serum albumin (HSA) and 50% glucose, both used for intravenous infusion into humans and both released after strict control for endotoxin content. The presence of AGE formed by HSA and glucose was confirmed using 2 independent assays. The inflammatory properties of these AGE were assessed using synthesis and release of the proinflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF) and IL-8, a chemokine. RESULTS: Alone, AGE did not induce these cytokines from peripheral blood mononuclear cells (PBMC) obtained from 14 healthy human donors. However, in the presence of 1 or 10 ng/ml of endotoxin, AGE augmented the production of IL-1 and TNF above that induced by endotoxin alone. Although the amount of augmentation of LPS-induced cytokines by AGE varied between the blood donors, the response was consistently observed and reached statistical significance. The augmentation of cytokine production was confirmed using AGE prepared with different lots of HSA and glucose. CONCLUSION: These results demonstrate that in the strict absence ofendotoxins, AGE are formed that do not stimulate cytokine production from PBMC of healthy donors, however, AGE significantly augment the synthesis and release of proinflammatory cytokine in the presence of low concentrations of endotoxins. The data suggest that renal replacement therapies should consider the role of microbial products in potentiating the biological consequences of naturally formed AGE and their potential to contribute to systemic and local inflammation in renal replacement therapies. Therefore, although the formation of AGE is unavoidable, excluding microbial products during renal replacement therapy should reduce the pathological consequences of AGE.

Adult↗
PubMed2003

Differences in the permeability of high-flux dialyzer membranes for bacterial pyrogens.

AIMS: The increasing use of high-flux membranes for hemodialysis has raised concerns that patients dialyzed with these membranes may be at higher risk of being exposed to cytokine-inducing bacterial substances in the dialysate than patients dialyzed with low-flux membranes. We investigated the permeability of various high-flux membranes for both purified E. coli lipopolysaccharide (LPS) as well as for LPS derived from Stenotrophomonas (Sten.) maltophilia. MATERIALS AND METHODS: An in vitro dialysis circuit with saline in the blood compartment of 3 dialyzers containing different membranes (polysulfone, helixone and Diapes) was employed. The dialysate was challenged with increasing doses of sterile filtrates derived from Sten. maltophilia cultures or with purified LPS from E. coli. Samples from the blood compartment were tested for cytokine induction (IL-1beta, IL-6 and TNF) in mononuclear cells as well as for LPS by limulus amebocyte lysate test (LAL). RESULTS: IL-6 induction above sterile controls (< 0.02 ng/ml IL-6) was observed by samples from the blood side of DIAPES dialyzers (1.2 +/- 0.7 ng/ml IL-6) after challenging the dialysate with 4.1 +/- 3.6 U/ml E. coli LPS (9.9 +/- 4.5 ng/ml IL-6). In contrast, at the same challenge dose no significant IL-6 induction above sterile controls was observed by blood side samples of polysulfone (0.15 +/- 0.07 ng/ml) and helixone (0.09 +/- 0.05 ng/ml) dialyzers. Increasing the amount of E. coli LPS in the dialysate further augmented IL-6 induction by blood side samples of Diapes but not of polysulfone and helixone dialyzers. Similar results were obtained for IL-1beta and TNF. After challenging the dialysate with E. coli LPS as well as with cultures of Sten. maltophilia, significantly more LAL reactivity was observed in the blood compartment of Diapes compared to polysulfone and helixone. CONCLUSIONS: There are considerable differences between high-flux membranes regarding their permeability for cytokine-inducing substances from E. coli as well as for LPS derived from E. coli and Sten. maltophilia. Dialyzers that leak CIS under aqueous conditions in vivo should not be used unless the dialysate has passed through an ultrafilter.

Escherichia coli Proteins↗
PubMed2000

Recombinant versus natural human 111In-beta2-microglobulin for scintigraphic detection of Abeta2m amyloid in dialysis patients.

BACKGROUND: We previously introduced scintigraphy with 131I-labeled beta2-microglobulin (beta2m), purified from uremic hemofiltrate, that is, "natural" beta2m, to specifically detect beta2m-associated amyloidosis (Abeta2m) in hemodialysis (HD) patients. METHODS: To improve the safety and resolution of the scan, we covalently bound the chelator diethylenetriaminepentaacetic acid to natural beta2m to allow radiolabeling with 111In. In a second step, we generated and evaluated the usage of recombinant human beta2m (rhbeta2m) for scintigraphy. RESULTS: Using natural 111In-labeled beta2m, eight patients on HD for 0 to 17 years, without evidence of Abeta2m, were scanned. Whole-body scintigraphy at 48 to 72 hours postinjection revealed no significant tracer accumulation over joint regions. In contrast, nine patients on HD for 10 to 21 years with clinical, radiological, or histologic (N = 4) evidence of Abeta2m showed selective tracer uptake over various joint regions. Tracer accumulation in visceral organs, which could not be related to tracer elimination or metabolism, was not detected. Compared with the previous 131I beta2m scan, scintigraphy with 111In-labeled beta2m offered highly improved image contrast, increased sensitivity, and a 50 to 70% reduction of the radiation exposure. Scanning with 111In-labeled recombinant human beta2m was performed in six patients: No significant tracer accumulation was observed over joint regions in two patients on short-term HD without evidence of Abeta2m; in contrast, local tracer accumulations similar to those observed with natural beta2m could be demonstrated in four long-term (10 to 27 years) HD patients with clinical, radiological, and histologic (N = 1) evidence of Abeta2m. CONCLUSION: Scintigraphy for Abeta2m with 111In-labeled rhbeta2m provides a homogenous and safe recombinant protein source and leads to enhanced sensitivity and lower radiation exposure.

Adult↗