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Biomedical subjects

B D Williams

Publications and source records attributed to B D Williams.

At least 37 records · Page 2Linked to original sources
PubMed1999

Liposomal clodronate eliminates synovial macrophages, reduces inflammation and ameliorates joint destruction in antigen-induced arthritis.

OBJECTIVES: To investigate the efficacy of a single i.v. dose of clodronate encapsulated within small unilamellar vesicles in suppressing joint inflammation and the histological progression of rat antigen-induced arthritis (AIA). METHODS: Rats with AIA received a single i.v. injection of 20 mg of clodronate encapsulated within small unilamellar vesicles (SUVc) or larger multilamellar vesicles (MLVc) 7 days post-arthritis induction. Free clodronate or saline were used as negative controls. RESULTS: SUVc was shown to be more effective than MLVc, sustaining a significant reduction in knee swelling for up to 7 days after the initial systemic administration. Knee swelling in free clodronate-treated animals was not significantly affected. The increased efficacy of SUVc in reducing inflammation and joint destruction was associated with a significant depletion of resident ED1+, ED2+ and ED3+ macrophages from the synovial membrane (SM). CONCLUSIONS: SUVc is more efficient than MLVc in reducing the severity of inflammation and joint destruction in rat AIA, and is associated with the specific elimination of macrophage subpopulations from the SM.

Analgesics, Non-Narcotic↗
PubMed1999

Monoclonal IgG antibodies influence the migration patterns of lymphocytes in vivo.

Monoclonal antibodies (MoAb) are useful therapeutic agents for the treatment of a variety of human disorders, although the effector mechanisms responsible for the outcome of an efficient immunotherapy remain unclear. This study was designed to address the early effects of MoAb on the migration patterns of lymphocytes in vivo. The clearance profiles and tissue distribution of 111In-labelled rat lymph node cells were examined in both normal and decomplemented allogeneic and semi-allogeneic recipients pre-injected with IgG2b (R3/13) or IgG2a (R2/15S) MoAb directed against the RT1Aa, the classical class I major histocompatibility complex antigen of the DA rat. Both MoAb were equally effective in not only augmenting the removal of DA and (DA x PVG)F1 cells from the circulation and promoting their subsequent localization within the liver but also causing a significant degree of cell lysis during the early phase of cell clearance, even in decomplemented recipients. Although R3/13 and R2/15S are known to target erythrocytes differently in normal and cobra venom factor (CVF)-treated animals, no differences were observed in the migration behaviour of lymph node cells in allogeneic or semi-allogeneic hosts pre-injected with the same MoAb. Since rat lymphocytes express a much higher level of the RT1Aa antigen as compared with erythrocytes, we could not exclude a possible role of residual complement components in the circulation of CVF-treated rats that may have accounted for the observed antibody-dependent effects on target lymphocytes. On the basis of these findings we believe that the design and methodology employed in our present experimental opsonization system were inadequate to define clearly the mechanisms responsible for antibody-mediated removal and destruction of target lymphocytes in vivo.

Animals↗
PubMed1999

Insulin action on muscle protein kinetics and amino acid transport during recovery after resistance exercise.

We have determined the individual and combined effects of insulin and prior exercise on leg muscle protein synthesis and degradation, amino acid transport, glucose uptake, and alanine metabolism. Normal volunteers were studied in the postabsorptive state at rest and about 3 h after a heavy leg resistance exercise routine. The leg arteriovenous balance technique was used in combination with stable isotopic tracers of amino acids and biopsies of the vastus lateralis muscle. Insulin was infused into a femoral artery to increase the leg insulin concentrations to high physiologic levels without substantively affecting the whole-body level. Protein synthesis and degradation were determined as rates of intramuscular phenylalanine utilization and appearance, and muscle fractional synthetic rate (FSR) was also determined. Leg blood flow was greater after exercise than at rest (P<0.05). Insulin accelerated blood flow at rest but not after exercise (P<0.05). The rates of protein synthesis and degradation were greater during the postexercise recovery (65+/-10 and 74+/-10 nmol x min(-1) x 100 ml(-1) leg volume, respectively) than at rest (30+/-7 and 46+/-8 nmol x min(-1) x 100 ml(-1) leg volume, respectively; P<0.05). Insulin infusion increased protein synthesis at rest (51+/-4 nmol x min(-1) x 100 ml(-1) leg volume) but not during the postexercise recovery (64+/-9 nmol x min(-1) x 100 ml(-1) leg volume; P<0.05). Insulin infusion at rest did not change the rate of protein degradation (48+/-3 nmol x min(-1) 100 ml(-1) leg volume). In contrast, insulin infusion after exercise significantly decreased the rate of protein degradation (52+/-9 nmol x min(-1) x 100 ml(-1) leg volume). The insulin stimulatory effects on inward alanine transport and glucose uptake were three times greater during the postexercise recovery than at rest (P<0.05). In contrast, the insulin effects on phenylalanine, leucine, and lysine transport were similar at rest and after exercise. In conclusion, the ability of insulin to stimulate glucose uptake and alanine transport and to suppress protein degradation in skeletal muscle is increased after resistance exercise. Decreased amino acid availability may limit the stimulatory effect of insulin on muscle protein synthesis after exercise.

Adult↗
PubMed1998

Alanine and glutamine kinetics at rest and during exercise in humans.

PURPOSE: The purpose of this study was to quantify both alanine and glutamine kinetics during exercise of moderate intensity to determine the sum total of alanine and glutamine flux. METHODS: Tracer methods were used to quantify alanine and glutamine rates of appearance (Ra) in plasma at rest and during 180 min of approximately 45% VO2max treadmill exercise in six normal volunteers (25 +/- 2 yr, 68 +/- 2.5 kg, VO2max 43 +/- 2.4 mL.min-1.kg-1; means +/- SE). Bolus injections (N = 3) or primed-constant infusions (N = 3) of 2H5-glutamine and 3-13C-alanine were given at rest on 1 d and 10-15 min after the onset of exercise on a separate day less than 2 wk later. Plasma enrichment decay curves and plateau enrichments were used to estimate alanine and glutamine kinetics. RESULTS: Whereas alanine Ra increased significantly from rest to exercise (5.72 +/- 0.31 vs 13.5 +/- 1.9 mumol.min-1.kg-1, respectively; P < 0.01), glutamine Ra was not significantly altered by exercise (6.11 +/- 0.44 and 6.40 +/- 0.69 mumol.min-1.kg-1 at rest and during exercise, respectively). The total of alanine and glutamine flux increased from 17.93 +/- 0.88 to 25.98 +/- 3.04 (P < 0.05). CONCLUSIONS: Since most muscle amino-N is released as alanine and glutamine, these findings provide strong evidence that amino-N delivery from muscle to the liver is increased during exercise. In addition, it appears that alanine, rather than glutamine, is the predominant N carrier involved in the transfer of N from muscle to the liver during moderate intensity exercise.

Adult↗
PubMed1997

Local therapy with soluble complement receptor 1 (sCR1) suppresses inflammation in rat mono-articular arthritis.

Complement activation has been implicated in the pathogenesis of human rheumatoid arthritis. We sought to determine whether inhibition of complement (C) using sCR1 could influence the development and progression of antigen arthritis in the rat, a recognized model of human chronic synovitis. The effect of C inhibition, systemically and locally, on three different stages of disease was examined: (i) prophylaxis, (ii) treatment of established inflammation, and (iii) prevention of antigen-induced flares of disease. Arthritis was assessed by knee swelling and by histological examination. Our results show that intra-articular injection of sCR1 prior to disease onset reduced joint swelling and development of arthritis, whereas systemic administration was ineffective. Treatment of established arthritis with intraarticular sCR1 3 days after disease onset caused a transient reduction in swelling, but treatment 7 days after disease onset had no effect on disease. An intra-articular dose of sCR1 given at the time of disease flares had a small, yet significant effect on knee swelling. We conclude that complement activation is important in the initiation and maintenance of inflammation in antigen arthritis. The potent effect of local C inhibition suggests that C biosynthesis and activation within the joint contributes to inflammation in this model of arthritis.

Animals↗
PubMed1997

Regulation of glucose production during exercise at 80% of VO2peak in untrained humans.

To determine whether alterations in insulin and/or glucagon secretion play an important role in stimulating glucose production (Ra) during intense but submaximal exercise, we studied six untrained subjects during 30 min of cycling at 80% of peak oxygen uptake on two occasions: once under control conditions and once when alterations in insulin and glucagon secretion were prevented with the use of the pancreatic islet clamp technique. In the latter experiments, glucose was infused during exercise to match glycemia with control levels. Glucose kinetics were measured in both trials using a primed, continuous infusion of [6,6-2H]glucose. In the control trial, glucose Ra rose from 11.9 +/- 0.8 mumol.min-1.kg-1 at rest to 42.5 +/- 4.3 mumol.min-1.kg-1 by the end of exercise. A similar increment was observed in the islet clamp experiments, with endogenous Ra peaking at 37.2 +/- 7.9 mumol.min-1.kg-1. This was true even through glucagon concentration did not change from basal and insulin concentration actually rose (the latter apparently due to a decrease in insulin clearance during intense exercise). Thus neither decrements in insulin or increments in glucagon are apparently required to stimulate glucose Ra under the present conditions. Because epinephrine levels rose only slightly, it appears that either neurally released norepinephrine or some other, as yet unidentified, factor is responsible for stimulating glucose Ra during intense but submaximal exercise.

Adult↗
PubMed1996

Silent myocardial infarction in Wegener's granulomatosis.

Histological cardiac abnormalities in Wegener's granulomatosis can frequently be demonstrated at post-mortem examination, but clinically significant cardiac involvement is rare. We describe a massive silent myocardial infarction leading to intractable heart failure and death in a young man with Wegener's granulomatosis, occurring at a time when other features of the disease were responding to aggressive immunosuppression.

Adult↗
PubMed1996

Iliopsoas bursitis-an unusual presentation of metastatic bone disease.

Diagnostic uncertainty concerning the nature of an enlarging inguinal mass in an elderly male with a short history of hip pain was resolved by a combination of ultrasound and magnetic resonance imaging (MRI). Subsequent investigations showed that the enlarged iliopsoas bursa, which contained a number of atypical cells, was an unusual presenting feature of a destructive metastatic lesion in the right hip.

Aged↗
PubMed1996

A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis.

In this study, we sought to determine whether liposomal preparations containing a phospholipid conjugate of methotrexate and dimyristoylphosphatidylethanolamine (MTX-gamma-DMPE) incorporated within their lipid membranes are effective in suppressing established joint inflammation in a monoarticular model of arthritis in the rat. Arthritis was induced in the right knee joint of Lewis rats. The rats were treated with a single intra-articular injection of either free methotrexate (MTX), liposomal MTX [MTX-multilamellar vesicles (MLV)-1.2 microns or MTX-small unilamellar vesicles (SUV)-100 nm], control liposomes (E-LIPO) or saline into the inflamed knee 7 days after arthritis induction. There was no significant difference in knee swelling in MTX-, saline- and E-LIPO-treated rats up to 21 days after treatment. However, MTX-MLV treatment produced a significant reduction in knee swelling (26.5 +/- 6.0%: mean +/- S.E.M.) 1 day after intra-articular injection compared with MTX (3.5 +/- 3.5%) and MTX-SUV (14.4 +/- 2.4%), respectively. Over the next 20 days, knee swelling in MTX-MLV-treated rats fell progressively and almost returned to normal. MTX-MLV treatment also inhibited the cellular infiltration associated with the arthritis. Large multilamellar liposomal preparations of MTX-gamma-DMPE are more effective than free MTX and MTX-SUV in suppressing inflammation. Their differential effects in treating the antigen-induced arthritis model are related to their retention within the joint space.

Animals↗
PubMed1996

Tyrosine phosphorylation in neutrophils from synovial fluid of patients with rheumatoid arthritis.

The priming of neutrophils is associated with an increase in the level of tyrosine phosphorylation of cytosolic proteins, specifically of proteins with mol. wts of 42 and 74 kDa. We show here, using dot blots and Western blotting, that neutrophils isolated from rheumatoid synovial fluid have increased tyrosine phosphorylation of these target proteins. The level of tyrosine phosphorylation within neutrophils in the synovial fluid was increased when compared with neutrophils from the blood of the same patients, normal blood or neutrophils from the synovial fluid of patients without rheumatoid arthritis. Neutrophils from the rheumatoid synovial fluid were also more active and were unable to be further primed by exogenous primers. These data suggest that this elevation of tyrosine phosphorylation was the result of the action of local priming agents within the rheumatoid synovial fluid.

Adult↗
PubMed1996

Signalling through neutrophil Fc gamma RIII, Fc gamma RII, and CD59 is not impaired in active rheumatoid arthritis.

OBJECTIVE: To compare neutrophil Fc receptor (Fc gamma R) and CD59 signalling responses in normal healthy subjects and patients with active rheumatoid arthritis (RA). METHODS: Intracellular free calcium concentrations were measured in neutrophils loaded with the fluorescent calcium indicator fura-2, using a spectrofluorimeter. RESULTS: Basal intracellular calcium ion concentrations were similar in both groups when no primary antibody, CD59, or CD32 (Fc gamma RIII) antibody was added. When CD16 (Fc gamma RIII) antibody was added, there was a significantly greater basal calcium concentration in the patient group compared with the control group. Transient cytosolic calcium ion fluxes were observed after binding Fc gamma RII, Fc gamma RIII, or CD59 with specific monoclonal antibodies and cross linking with the F(ab)2 fragment of sheep antimouse IgG. Peak concentrations of intracellular free calcium, [Ca2+]i, after cross linking each of the three receptors, were comparable between normal healthy donors and patients with RA. The lag period between addition of cross linking antibodies and the increase in calcium was also similar between normal individuals and patients. CONCLUSION: Contrary to previous reports, these results demonstrate that Ca2+ signalling responses of cross linked Fc receptors in blood neutrophils from patients with RA are identical to those in neutrophils of normal subjects. Signalling responses of cross linked CD59 are also unaltered.

Acute Disease↗
PubMed1996

Gut proteolysis contributes essential amino acids during exercise.

Arteriovenous difference and tracer dilution techniques were utilized to determine the effect of exercise on whole body, gut, liver, and splanchnic leucine kinetics. Five postabsorptive dogs were infused with [1-13C]leucine and studied during rest, 90 min of moderate-intensity treadmill exercise (1st 45 min, early; last 45 min, late exercise), and 90 min of recovery. The whole body leucine rate of appearance (Rai; mumol.min 1.kg-1) increased from rest (3.33 +/- 0.11) during early (3.68 +/- 0.14) and late (4.24 +/- 0.27, P < 0.05) exercise and was 3.41 +/- 0.19 during recovery. Gut Ra increased from rest (0.64 +/- 0.08) during early (0.92 +/- 0.12) and late (1.30 +/- 0.20, P < 0.05) exercise and was 0.77 +/- 0.16 during recovery. Liver leucine Ra did not significantly change (P > 0.05). The whole body leucine rate of disappearance (Rd) paralleled whole body leucine Ra throughout. Leucine Rd across the gut, liver, and splanchnic bed, however, did not significantly change (P > 0.05), indicating an increase in leucine uptake outside of these regions. Because active skeletal muscle is likely the principal consumer of these amino acids, the data suggest that gut protein-derived amino acids are utilized for the attenuation of net muscle protein catabolism during and immediately following exercise.

Amino Acids↗
PubMed1996

Muscle protein metabolism in female swimmers after a combination of resistance and endurance exercise.

There is little known about the responses of muscle protein metabolism in women to exercise. Furthermore, the effect of adding resistance training to an endurance training regimen on net protein anabolism has not been established in either men or women. The purpose of this study was to quantify the acute effects of combined swimming and resistance training on protein metabolism in female swimmers by the direct measurement of muscle protein synthesis and whole body protein degradation. Seven collegiate female swimmers were each studied on four separate occasions with a primed constant infusion of ring-[13C6]phenylalanine (Phe) to measure the fractional synthetic rate (FSR) of the posterior deltoid and whole body protein breakdown. Measurements were made over a 5-h period at rest and after each of three randomly ordered workouts: 1) 4,600 m of intense interval swimming (SW); 2) a whole body resistance-training workout with no swimming on that day (RW); and 3) swimming and resistance training combined (SR). Whole body protein breakdown was similar for all treatments (0.75 +/- 0.04, 0.69 +/- 0.03, 0.69 +/- 0.02, and 0.71 +/- 0.04 mumol.min-1.kg-1 for rest, RW, SW, and SR, respectively). The FSR of the posterior deltoid was significantly greater (P < 0.05) after SR (0.082 +/- 0.015%/h) than at rest (0.045 +/- 0.006%/h). There was no significant difference in the FSR after RW (0.048 +/- 0.004%/h) or SW (0.064 +/- 0.008%/h) from rest or from SR. These data indicate that the combination of swimming and resistance exercise stimulates net muscle protein synthesis above resting levels in female swimmers.

Adult↗
PubMed1995

Methods for assessing splenic macrophage depletion by liposome encapsulated clodronate.

Small unilamellar vesicles containing clodronate (SUVc) injected intravenously will deplete splenic macrophages and the degree of histological depletion can be assessed by determining the clearance and uptake of monoclonal antibody coated erythrocytes. Splenic Fc dependent clearance, assessed in decomplemented animals, provides a more sensitive index of the effects of large multilamellar liposome encapsulated clodronate (MLVc) and SUVc than does the clearance of complement coated erythrocytes on macrophage depletion in the spleen. MLVc were more efficient than SUVc in inducing a reduction in the number of red pulp macrophages within the spleen. Receptor specific red cell uptake in the spleen could be used as an alternative to histology when assessing splenic macrophage depletion. Encapsulation of clodronate is crucial to its depleting effect since the free drug in saline does not change splenic macrophage number or function.

Animals↗
PubMed1995

The effect of liposomally conjugated methotrexate upon mediator release from human peripheral blood monocytes.

The ability of methotrexate (MTX) and a liposomal preparation containing a lipophilic conjugate of methotrexate (MTX-LIPO) to modulate pro-inflammatory mediator release from lipopolysaccharide-stimulated human peripheral blood monocytes was investigated. At non-toxic concentrations MTX-LIPO (10 micrograms MTX per 250 micrograms lipid) was a potent inhibitor of both IL-1 beta and TNF release resulting in 70.07 +/- 2.3% and 59.19 +/- 2.36% (mean +/- S.E.M.) inhibition, respectively, whereas empty liposomes (E-LIPO; 250 micrograms lipid/well) of the same lipid composition and free MTX (up to 100 micrograms/well) had no effect on either mediator.

Cell Survival↗