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Biomedical subjects

J D Williams

Publications and source records attributed to J D Williams.

At least 145 records · Page 8Linked to original sources
PubMed1993

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Adolescent↗
PubMed1993

Human peritoneal mesothelial cells synthesize interleukin-6: induction by IL-1 beta and TNF alpha.

Recent studies have demonstrated increased levels of IL-6 in the peritoneal cavity during CAPD peritonitis. The current investigation was initiated (i) to examine the human peritoneal mesothelial cell (HPMC) as a possible source of this secreted IL-6 and (ii) to characterize the released product and examine its regulation by other cytokines. Unstimulated HPMC under growth arrested conditions released IL-6 in a time dependent manner. After 24-hour HPMC IL-6 release (mean +/- SEM, N = 13) (expressed as pg/micrograms cell protein) was 1.67 +/- 0.33. Stimulation of HPMC with IL-1 beta or TNF alpha resulted in a time (increasing up to 48 hr) and dose dependent IL-6 generation. After 24 hours the levels induced by IL-1 beta and TNF alpha (both at 1000 pg/ml) were (mean +/- SEM, N = 13) 19.08 +/- 2.98 and 6.62 +/- 1.72, respectively. Stimulation with combinations of IL-1 beta and TNF alpha resulted in additive increases in IL-6 release. This release could be inhibited by co-incubation with anti-IL-1 beta and/or anti-TNF alpha antibodies. The level of released HPMC IL-6 measured by immunometric assay (ELISA) correlated directly with that detected in the 7TD1 IL-6 bioassay (r = 0.63; P < 0.001). Western blot analysis of concentrated HPMC supernatants using specific anti-IL-6 antibody demonstrated immunoreactive bands at 23 and 28 Kd following IL-1 beta or TNF alpha treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1993

Comparison of macrolide antibiotics.

Macrolides have been in use since the early 1950s. In recent years new macrolides have been developed to try to overcome the problems associated with erythromycin. In general they have fairly similar in-vitro activity, although azithromycin has superior activity against Haemophilus influenzae and some Gram-negative organisms. Clarithromycin shows superior in-vitro activity against Legionella spp. and against the type strain of Chlamydia pneumoniae. The pharmacology of macrolides produces many interpretive problems, and macrolides show marked variation in their pharmacokinetic parameters, tissue affinity and intracellular penetration. Newer macrolides such as clarithromycin, roxithromycin, dirithromycin and azithromycin only need to be taken once or twice a day, which is likely to improve patient compliance. Few objective side-effect studies have been performed with the newer macrolides. Clinical efficacy studies are essential to elucidate the significance of the complex pharmacology of macrolides.

Absorption↗
PubMed1993

Common swine leucocyte antigen (SLA) haplotypes in NIH and Sinclair miniature swine have similar effects on the expression of an inherited melanoma.

Mixed lymphocyte culture and serological typing of NIH and Sinclair miniature swine indicate that the two herds share a common SLA haplotype. NIH haplotype a (International Haplotype H10) appears identical to Sinclair haplotype B, which has significant effects on the penetrance of Sinclair swine cutaneous malignant melanoma (SSCM). Offspring of crosses between melanoma-bearing Sinclair swine homozygous for the B haplotype and non-melanoma NIH aa swine have tumour incidence identical to Sinclair melanoma BB x Sinclair non-melanoma BB offspring. Our results provide further support for the involvement of the swine leucocyte antigen (SLA) complex in the inheritance of SSCM, and identify a new source of non-tumour animals that have all of the genes for SSCM except those at the tumour-initiator locus.

Animals↗
PubMed1993

Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise.

The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.

Adolescent↗
PubMed1993

Preservation of renal haemodynamic response to an oral protein load in non-insulin-dependent diabetes mellitus.

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2 h prior to and 3 h following the ingestion of a 1.2 g kg-1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean +/- SD): 7.2 +/- 2.0 mmol l-1; glycosylated haemoglobin: 8.1 +/- 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m2 surface area) were 83 +/- 10 and 410 +/- 76 ml min-1 for the Type 2 diabetic patients and 86 +/- 11 and 405 +/- 113 ml min-1 for the normals. GFR increased by 38 +/- 8 and 32 +/- 15% in the diabetic patients and normals, to 108 +/- 25 and 105 +/- 26 ml min-1 (p < 0.01 vs baseline). Peak ERPF was 501 +/- 127 and 476 +/- 119 ml min-1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.

Adult↗
PubMed1993

A potential role for endogenous adenosine in control of human glomerular and tubular function.

Adenosine has profound effects on renal function in experimental animals, but little is known about its role in human subjects. The recent advent of specific adenosine agonists and antagonists suitable for human use, however, now makes it possible to evaluate the influence of this potent vasoactive compound in both normal and pathological states. In this study we assessed the effects of FK-453, a nonxanthine, selective adenosine A1-receptor antagonist, on normal renal hemodynamics, tubular function, and plasma renin release. Eight healthy, male subjects each received three single oral doses of FK-453 (50, 100, and 200 mg) in ascending dose order with random allocation of one matched placebo dose, each on a separate study day. Renal hemodynamics, tubular function, and plasma renin concentrations (PRC) were assessed at baseline and postdose on each study day. Glomerular filtration rate (clearance of 51Cr-labeled EDTA) rose by 18.0%, 3 h after the administration of 100 mg of FK-453 and by 18.3% and 23.5%, 2 and 3 h, respectively, after the 200-mg dose, which was significantly different from the changes following placebo. There were no significant changes in mean arterial blood pressure or effective renal plasma flow (clearance of 125I-Hippuran). In contrast there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional excretions of sodium, phosphate, bicarbonate, chloride, magnesium, and uric acid in response to FK-453. No glycosuria or aminoaciduria was detected on urinalysis. There was, in addition, a marked increase in PRC in response to FK-453.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1993

Peritoneal dialysis fluid inhibition of polymorphonuclear leukocyte respiratory burst activation is related to the lowering of intracellular pH.

In order to elucidate the mechanism of peritoneal dialysis fluid inhibition of cell functions, laboratory-prepared fluids were used to investigate the specific influences of low pH and high lactate concentration on neutrophil viability, phagocytosis, respiratory burst activation and leukotriene B4 (LTB4) generation. In the absence of any reduction of viability, respiratory burst activation, stimulated by serum-treated zymosan (STZ), was significantly inhibited by fluids of low pH containing high concentrations of sodium lactate. Neither low pH nor lactate concentration alone, however, caused significant suppression of this parameter of cell activation. Under the same conditions, the phagocytosis of STZ was partially inhibited in a lactate- and pH-dependent manner. In contrast, the generation of LTB4 in response to STZ was unaffected by pH and lactate concentration. The incubation of polymorphonuclear leukocytes (PMN) in fluids containing 35 mM lactate at pH 5.2 resulted in an immediate and profound lowering in intracellular pH ([pH]i) which was not observed in lactate-containing fluids at neutral pH or at low pH in the absence of lactate. We postulate that the critical lowering of [pH]i in PMN, caused by the combination of high lactate concentration and low pH of the dialysis fluids, is responsible for the observed inhibition of respiratory burst activation. It is also possible that under these conditions, the lactate ion acts as a proton carrier across the cell membrane following the [H+] gradient. The time course of this [pH]i change suggests that host defence mechanisms may be impaired following short-time exposure to unused dialysis fluid prior to its equilibration in vivo.

Cells, Cultured↗
PubMed1993

Intraperitoneal phosphatidylcholine levels in patients on continuous ambulatory peritoneal dialysis do not correlate with adequacy of ultrafiltration.

A qualitative and quantitative study was undertaken to determine the lipid composition of dialysate effluent from patients maintained on continuous ambulatory peritoneal dialysis (CAPD). Effluent, after a 4-h, 2.27% dextrose dwell, was collected on ice, centrifuged and extracted for lipids with chloroform and methanol. Lipids were separated and identified by thin layer chromatography, and the constituent fatty acids were quantitated by gas liquid chromatography. Effluents from 10 patients were assayed at the commencement of CAPD treatment and again after 6 months of therapy. There was a significant fall in phosphatidylcholine and phospholipid concentrations (P < 0.007) with time, whereas the fatty acid compositions of these lipids remained constant. Dialysate phosphatidylcholine and phospholipid concentrations were not significantly different between seven patients with poor ultrafiltration and eight patients who had normal fluid removal. This study demonstrates that there is no relationship between dialysate phospholipid levels and the adequacy of filtration, although it corroborates previous reports of an inverse correlation between time on CAPD and dialysate lipid concentrations. These results do not support a rationale for ip phosphatidylcholine administration in patients with poor ultrafiltration.

Adult↗
PubMed1993

Peritoneal dialysis fluid inhibition of phagocyte function: effects of osmolality and glucose concentration.

Solutions were formulated to examine, independently, the roles of osmolality and glucose in the reduction of viability and inhibition of phagocyte function by dextrose-containing peritoneal dialysis fluids. The exposure of neutrophils (polymorphonuclear leukocytes) to test fluids containing > or = 2.7% (wt/vol) glucose resulted in significant cytotoxicity as assessed by the release of lactate dehydrogenase above control values (7.12 +/- 2.65%). At the highest concentration of glucose (4.5%), lactate dehydrogenase release was 15.83 +/- 0.49% (P < 0.05). These effects were directly related to the presence of D-glucose in the test fluids. In contrast, phagocytosis and the release of leukotriene B4 from PMN stimulated with serum-treated zymosan were significantly inhibited in an osmolality-, but not glucose-, dependent manner. The inhibition of tumor necrosis factor alpha and interleukin-6 release from mononuclear leukocytes was inhibited by a combination of osmolality and monosaccharide concentration. Under the same conditions, PMN respiratory burst activation remained unaffected irrespective of glucose concentration or fluid osmolality. These data indicate that, in addition to the low pH of peritoneal dialysis fluid and its high lactate concentration, its glucose content (either directly or as a consequence of the resulting hyperosmolality of the fluid) inhibits cell functional parameters. These findings suggest clinically significant inhibition of host defense mechanisms because, in high-glucose dialysis fluids, osmolality does not reach physiologic values, even during extended intraperitoneal dwell periods.

Cell Survival↗
PubMed1993

Immunolocalization and characterization of the rat analogue of human CD59 in kidney and glomerular cells.

CD59, a potent inhibitor of the human membrane attack complex (MAC) of complement, is present on many different tissues throughout the body. Recently we identified and characterized the rat analogue of CD59 and produced a number of monoclonal antibodies (mAb). We have now used these antibodies to demonstrate, by immunofluorescence microscopy, that rat CD59 was widely expressed in the rat kidney. Staining of renal sections revealed the presence of rat CD59 in abundance in the glomerulus, collecting ducts and distal tubules. Staining was abolished by treatment of sections with phosphatidylinositol-specific phospholipase C (PIPLC). Rat mesangial cells also stained strongly for rat CD59, giving an intensely granular staining pattern. In complement attack experiments the cultured mesangial cells were rendered more susceptible to lysis by rat or human complement after preincubation with the anti-inhibitor mAb. The results demonstrate that the rat analogue of CD59 is present and functionally active in rat renal tissue. The protective effect of CD59 against MAC-mediated tissue injury can now be examined in rat models of human renal disease.

Animals↗
PubMed1993

Cross-linking of CD11b or CD18 signals release of localized Ca2+ from intracellular stores in neutrophils.

Cross-linking of antibodies bound to CD11b or CD18 on the neutrophil surface produced a large Ca2+ transient (max. approximately 500 nM). The major source for this Ca2+ rise (more than 81%) was from an intracellular Ca2+ store. After integrin cross-linking, the Ca2+ transient induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP) was decreased, suggesting that both stimuli acted on the same Ca2+ store. Release from the Ca2+ store, induced by integrin cross-linking, was visualized as a 'cloud' of elevated Ca2+, which remained localized even in the presence of extracellular Ca2+. The generation of localized cytosolic Ca2+ signals by cross-linking integrin may be important for triggering localized cellular responses.

Antigens, CD↗
PubMed1993

Low-dose cyclosporin nephrotoxicity in the rat.

The nephrotoxicity of cyclosporin (CsA) continues to be a clinical problem that detracts from its obvious benefits as an immunosuppressive agent. Animal models designed to study the problem have generally relied either on chronic administration of high doses of the drug or acute administration of single i.v. doses. The present study establishes a model of CsA nephrotoxicity using doses of the drug comparable to those used in man administered over a time period sufficient for haemodynamic and structural changes to become evident. The technique used measures glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) by the plasma clearance of chromium EDTA and iodohippuran respectively. This has the advantage of allowing sequential measurements in individual animals. Significant impairment of GFR was seen in animals treated intraperitoneally with doses of CsA as low as 5 mg/kg/day. CsA 7.5 mg/kg/day caused a significant reduction in ERPF, and at 10 mg/kg/day and greater filtration fraction also declined significantly. Detailed histological examination of the kidneys from these animals also revealed significant tubular dilatation at 10 mg/kg/day and above. This model of CsA toxicity circumvents many of the problems associated with other models. The animals can be studied longitudinally and the period of administration has relevance to clinic practice. This work provides the basis for further studies which can closely mimic the clinical situation using doses similar to those used for human maintenance immunosuppression.

Animals↗
PubMed1993

Directionally selective mnemonic properties of neurons in the lateral dorsal nucleus of the thalamus of rats.

The hippocampal formation has been extensively studied for its special role in visual spatial learning and navigation. To ascertain the nature of the associations made, or computations performed, by hippocampus, it is important to delineate the functional contributions of its afferents. Therefore, single units were recorded in the lateral dorsal nucleus of the thalamus (LDN) as rats performed multiple trials on a radial maze. Many LDN neurons selectively discharged when an animal's head was aligned along particular directions in space, irrespective of its location in the test room. These direction-sensitive cells were localized to the dorsal aspect of the caudal two-thirds of the LDN, the site of innervation by retinal recipient pretectal and intermediate/deep-layer superior colliculus cells (Thompson and Robertson, 1987b). The directional specificity and preference of LDN cells were disrupted if rats were placed on the maze in darkness. If the room light was then turned on, the original preference was restored. If the light was again turned off, directional firing was maintained briefly. Normal directional firing lasted about 2-3 min. After this time, the directional preference (but not specificity) appeared to "rotate" systematically in either the clockwise or counterclockwise direction. The duration of normal directional discharge patterns in darkness could be extended to 30 min by varying the behavior of the animal. LDN cells required visual input to initialize reliable directional firing. After the rat viewed the environment, directional specificity was maintained in the absence of visual cues. Maximal directional firing was achieved only when the rat viewed the entire test room, and not just the scene associated with the directional preference of the cell. Thus, contextual information seems important. Also, a significant correlation was found between directional specificity and errors made on the maze during acquisition of the task. It was concluded that the LDN may pass on to the hippocampal formation directional information that is not merely a reflection of current sensory input. As such, the LDN may serve an important integrative function for limbic spatial learning systems.

Animals↗
PubMed1993

Release of gelatinase and superoxide from human mononuclear phagocytes in response to particulate Tamm Horsfall protein.

This study describes the in vitro activation of human mononuclear phagocytes by particulate Tamm Horsfall protein (THP). Peripheral blood monocytes phagocytosed THP particles with the accompanying release of superoxide radicals, N-acetyl-beta-D-glucosaminidase, and neutral metalloproteinase. Immunoprecipitation and substrate gel analysis identified the neutral proteinase as a 95-kd gelatinase. A comparison with other particulate ligands highlighted the specificity of the response to THP and showed that the magnitude of the response was comparable with that obtained with lipopolysaccharide (100 micrograms/ml). Parallel studies using peritoneal macrophages resulted in a similar pattern of enzyme release and reactive oxygen species synthesis. THP has been implicated in the pathogenesis of tubulointerstitial nephritis associated with reflux nephropathy. The present study indicates that an inflammatory response initiated by a neutrophil-THP interaction may be extended into a chronic phase via the activation of mononuclear phagocytes. The subsequent release of reactive oxygen metabolites and proteinases may contribute to the tissue damage and fibrosis associated with chronic immune-mediated tubulointerstitial nephritis.

Chemical Precipitation↗
PubMed1993

Cell function and viability in glucose polymer peritoneal dialysis fluids.

OBJECTIVE: To investigate the biocompatibility profile of a new peritoneal dialysis fluid containing glucose polymer (GPF). DESIGN: Viability and function of peripheral neutrophils (PMN) from healthy donors and cultured human peritoneal mesothelial cells were assessed in vitro after exposure to dialysis fluids. Phagocytosis, leukotriene B4 synthesis, and respiratory burst activation were measured following stimulation with serum-treated zymosan (STZ) or opsonized Staphylococcus epidermidis (S. epidermidis). Bacterial growth in the fluids was also investigated. In vivo pH equilibration of GPF and subsequent respiratory burst activation following incubation in spent dialysate were studied. RESULTS: For all the host defense parameters measured, commercial dialysis fluids (Dianeal; 1.36% and 3.86% glucose) and GPF (pH 5.2) were significantly more inhibitory than the control buffer (pH 7.3). Mesothelial cell viability was reduced by all the fluids tested irrespective of pH. Glucose polymer fluid was significantly more inhibitory than Dianeal 1.36% for STZ phagocytosis and respiratory burst activation. In contrast, it was less suppressive than Dianeal 3.86% for LTB4 synthesis. For all parameters tested, except LTB4 generation, there was a marked effect of pH, with GPF being significantly more inhibitory at pH 5.2 than at pH 7.3. None of the fluids tested supported the growth of S. epidermidis, although the viable counts in GFP were significantly higher than in Dianeal. Fluid inhibition of PMN respiratory burst activation and cytotoxicity were reduced in a time-dependent manner following increasing dwell time in vivo. CONCLUSIONS: GPF does not appear to be significantly different from Dianeal as far as host defense parameters are concerned. However, the cell viability and bacterial survival data suggest some possibly negative aspects of this fluid formation.

Biocompatible Materials↗