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Biomedical subjects

R G Russell

Publications and source records attributed to R G Russell.

At least 163 records · Page 9Linked to original sources
PubMed1989

The effect of tumor necrosis factor alpha and gamma-interferon on the resorption of human articular cartilage and on the production of prostaglandin E and of caseinase activity by human articular chondrocytes.

In cultured human articular chondrocytes, addition of tumor necrosis factor alpha (TNF alpha) stimulated caseinase activity over the range of 10(-11) M to 10(-7) M and stimulated prostaglandin E (PGE) production over the range of 10(-10) M to 10(-7) M. Maximal stimulation was observed at 10(-8)M TNF alpha for both activities. Gamma-interferon (gamma-IFN) had a variable effect on PGE production and no significant effect on caseinase activity in articular chondrocyte cultures over a concentration range of 0.1-1,000 units/ml. Co-incubation of TNF alpha with gamma-IFN enhanced PGE production and decreased caseinase activity. Concentrations as low as 1 unit/ml of gamma-IFN had significant effects on TNF-stimulated production of PGE and on caseinase activity. Resorption of human articular cartilage was stimulated by TNF alpha (10(-7) M) and was inhibited by gamma-IFN (1,000 units/ml). It is possible that cartilage breakdown in vivo may be modulated by such interactions between cytokines.

Cartilage, Articular↗
PubMed1989

Experimental Campylobacter jejuni infection in Macaca nemestrina.

Experimental infection of four specific-pathogen-free Macaca nemestrina monkeys (aged 3.5 and 4.5 months) with Campylobacter jejuni 81-176 caused acute diarrheal illness, characterized by fluid diarrhea, bloody stools, and fecal leukocytes, which lasted for approximately 7 to 11 days. Histologic examination of intestinal biopsies showed acute colitis characterized by infiltration of the mucosa with neutrophils and lymphocytes, and cryptitis. There were no histologic changes in the small intestine. Excretion of C. jejuni was demonstrated for 2 to 4 weeks postchallenge. Plasma antibodies to C. jejuni group antigen were elevated after challenge. Only mild diarrhea occurred after rechallenge with the same strain or with a heterologous C. jejuni strain (79-168) followed by further elevation in specific immunoglobulins A, M, and G. Four 1-year-old juvenile M. nemestrina monkeys which had experienced multiple infections with Campylobacter spp. did not exhibit illness when challenged with C. jejuni 81-176. All had elevated immunoglobulin A, M, and G plasma antibodies prior to challenge, and these humoral antibody levels were indicative of the immunity to challenge. The results demonstrate that C. jejuni infection in M. nemestrina caused colitis with clinical and pathologic results similar to those found in humans and indicate that prior infection protects against subsequent challenge.

Animals↗
PubMed1989

Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.

Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative potencies as they inhibit bone resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human marrow cultures, and that this may be related to their ability to inhibit bone resorption in vivo.

Bone Marrow↗
PubMed1988

Theoretical interpretation of isotope labelling experiments in cells in which the label is chemically incorporated: the example of orthophosphate.

Studies of transport across the plasma membrane in intact cells frequently involve measuring the incorporation of a labelled extracellular species into the cells. Unfortunately, if the labelled species is metabolized in the cell, the kinetics of labelling are made more complicated. Using the example of the incorporation of 32P-labelled orthophosphate into cells, we describe a mathematical model which allows for this complication, and show how this may alter the interpretation of experiments. The analysis is widely applicable to cellular labelling studies with any species that undergoes chemical exchange with a large cellular pool.

Animals↗
PubMed1988

Evidence that ecto-nucleoside-triphosphate pyrophosphatase serves in the generation of extracellular inorganic pyrophosphate in human bone and articular cartilage.

Extracellular inorganic pyrophosphate (PPi) is important in the regulation of mineralisation of bone, and in the pathogenesis of chondrocalcinosis, an arthritic disease in which calcium pyrophosphate dihydrate crystals form in articular cartilage. Nucleoside-triphosphate pyrophosphatase, which catalyses the formation of PPi, was previously observed at the surface of human articular chondrocytes in culture. A similar enzyme has been identified in osteoblast-like human bone cells in culture, and is active towards purine and pyrimidine nucleoside triphosphates. The enzyme has high affinity for ATP and is located on the cell surface, and thus could serve in the generation of extracellular PPi. Moreover, no other mechanism for the catabolism of small amounts of exogenous ATP is present in human bone cells. Further evidence for ecto-nucleoside-triphosphate pyrophosphatase serving in the generation of extracellular PPi in articular cartilage and bone was obtained by studying the ability of alternative substrates (which do not yield PPi) to inhibit generation of PPi from ATP. In both articular chondrocytes and bone cells, the enzyme exhibited an apparent preference for ATP over dinucleotide and phosphodiester substrates. Some potential inhibitors of the enzyme activity were also studied in both cell types. ADP moderately inhibited the activity but two bisphosphonate drugs were only slightly inhibitory.

Bone Matrix↗
PubMed1988

Regulation of phosphate metabolism in human red cells following prolonged incubation to steady state in vitro.

Human red cells were incubated aseptically in vitro for 24 or 48 h to allow the cellular concentrations of orthophosphate (Pi) and organic phosphates to attain steady state. In plasma at pH 7.0-8.0, the transmembrane Pi concentration ratio R (cellular Pi/plasma Pi) decreased with increasing pH, with a slope which was 2.7-times greater than that predicted if Pi simply distributed passively across the cell membrane. The concentration of 2,3-bisphosphoglycerate (2,3-BPG), the most abundant cytosolic organic phosphate, decreased at acidic pH and increased at alkaline pH, but stabilised at these values after 24 h. Therefore, while net generation or consumption of Pi by 2,3-BPG may initially have contributed to the steep dependence of R on pH, some other factor must have maintained this anomaly after 24 h. In plasma in which the Pi concentration was increased from 1 to 2.5 mM, the cellular Pi concentration increased from 0.6 to only 1.0 mmol/l cells, and 2,3-BPG increased by less than 20%. Thus, cellular Pi and 2,3-BPG concentrations seemed to be buffered or regulated in the face of changes in extracellular Pi. However, this regulation failed in a Pi-free balanced salt solution, as the 2,3-BPG concentration declined to half that observed in freshly drawn blood, although cell Pi remained at about 0.3 mM. Incubation in Pi-free solution with ouabain for 24 h to decrease the transmembrane sodium gradient, or incubation for 2 h in the absence of sodium, decreased this residual cellular Pi by about 20%, but did not abolish it. In Pi-free solution, but not with 1 mM Pi, cellular Pi increased when passive transmembrane Pi leakage was inhibited with 4-acetamido-4'-iso-thiocyanatostilbene-2,2'-disulphonate (SITS). We conclude that red cell Pi concentration cannot be explained fully by passive transmembrane distribution of Pi, nor by changes in 2,3-BPG, and that part of the anomaly may arise from sodium-linked active Pi transport.

2,3-Diphosphoglycerate↗
PubMed1988

Net fluxes of orthophosphate across the plasma membrane in human red cells following alteration of pH and extracellular Pi concentration.

Even though net fluxes of Pi (orthophosphate) across the cell membrane may be important in clinical disorders involving the abnormal extracellular Pi concentration, in acid-base disturbances, and in the responses of some cells to hormones, relatively few studies have been made of these fluxes, owing to the complexities of interpretation. Here we have studied net fluxes in response to changes in extracellular pH and Pi concentration in the simple case of the human red cell. The permeability of the cell membrane to net Pi fluxes was described in terms of a first-order rate constant, epsilon. By means of a mathematical model, it was possible to discriminate between transmembrane Pi movement, net intracellular generation or consumption of Pi by organic phosphates, and extracellular generation of Pi from the cells lysing during the experiment. We show that net Pi influx into the cell during experimental alkalosis was probably driven by net consumption of Pi by organic phosphates, and that this was reversed during acidosis. Inhibition of net Pi influx by 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulphonate (SITS) suggests that, like Pi self-exchange, net influx is at least partly mediated by the band 3 transport protein. Unexpectedly, epsilon increased from 2 h-1 at extracellular pH 7.4 to approx. 7 h-1 at pH 7.8. From the value of epsilon at pH 7.4, we conclude that the apparent buffering or regulation of steady-state Pi concentrations, previously reported in red cells in vitro, was not an artifact of intracellular generation of Pi from organic phosphates.

Erythrocyte Membrane↗
PubMed1988

Actions of recombinant human gamma-interferon and tumor necrosis factor alpha on the proliferation and osteoblastic characteristics of human trabecular bone cells in vitro.

Using cultured human osteoblast-like cells, we studied the effects of tumor necrosis factor (TNF) and recombinant human gamma-interferon (gamma-IFN) on osteoblast growth and function, and demonstrated that TNF stimulated bone cell proliferation and prostaglandin production while inhibiting 1,25-(OH)2D3-stimulated alkaline phosphatase activity and osteocalcin release. In contrast, gamma-IFN inhibited proliferation and stimulated alkaline phosphatase activity of the cells, while inhibiting 1,25-(OH)2D3-stimulated osteocalcin production and having variable effects on the release of prostaglandins, depending on the presence of other factors. Our results suggest that TNF and gamma-IFN can act directly on bone-forming cells to affect both their proliferation and their differentiated function, and that changes in the ability of cells to produce these factors in disease states may contribute to alterations in the integrity of connective tissue matrices.

Alkaline Phosphatase↗
PubMed1988

Contrasting effects of intravenous and oral etidronate on vitamin D metabolism in man.

1. We have studied the early effects of intravenously and orally administered etidronate on vitamin D metabolism and indirect indices of calcium and skeletal metabolism in 17 patients with Paget's disease of bone. 2. Administration of etidronate by mouth (700-1400 mg daily for 1 month) or its intravenous infusion (300 mg daily for 5 days) decreased bone resorption as judged by urinary excretion of hydroxyproline and significantly increased renal tubular reabsorption of phosphate. No significant change in serum activity of alkaline phosphatase was noted with either regimen. 3. When etidronate was given by mouth there was a progressive decrease in fasting urinary calcium excretion and a rise in serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. In contrast, intravenous etidronate decreased serum values of 1,25-(OH)2D3 and was associated with a progressive increase in fasting calcium excretion, suggesting a decrease in the net influx of calcium from the extracellular compartment to bone. Significant inverse correlations were noted between the change induced in 1,25-(OH)2D3 values at 2 weeks and the changes in serum calcium, phosphate and fasting urinary excretion of calcium. 4. These observations suggest that the different effects of intravenous and oral etidronate on 1,25-(OH)2D3 values are a consequence of different doses of etidronate used and the different effects of these regimens on the accretion of calcium into bone.

Administration, Oral↗
PubMed1988

Effects of the anabolic steroid stanozolol on cells derived from human bone.

1. In this study, cells derived from explants of human trabecular bone were treated with the anabolic steroid stanozolol in order to determine whether the potential therapeutic effect of this agent might be explained by direct effects on skeletal tissue. 2. Stanozolol at a concentration of 10(-10) mol/l to 10(-6) mol/l consistently stimulated the incorporation of [3H]thymidine into DNA of human bone cells and increased proliferation. 3. Stanozolol had variable effects on the expression of two other markers of the osteoblast phenotype, namely the bone-specific vitamin-K-dependent protein osteocalcin, and the enzyme alkaline phosphatase. Although stanozolol tended to increase the values, this was not seen in all experiments. 4. We conclude that human bone cells respond to stanozolol. The effects of this agent on cell proliferation may be important in understanding the mode of action of this drug in the treatment of osteopenic disorders.

Adult↗
PubMed1988

Hypophosphatasia: biochemical screening of a Dutch kindred and evidence that urinary excretion of inorganic pyrophosphate is a marker for the disease.

Hypophosphatasia is an inherited disease in which a deficiency of the bone/liver/kidney or tissue nonspecific isoenzyme of alkaline phosphatase (AP; EC 3.1.3.1) occurs. All forms of the disease are characterized clinically by defective mineralization. Several biochemical abnormalities are associated with the deficiency of AP activity, e.g., increased urinary excretion of inorganic pyrophosphate (PPi) and phosphoethanolamine (PEA). Measurement of these analytes in kindreds of patients with hypophosphatasia may be useful in identifying carriers, and in understanding the inheritance of the disease. We studied biochemically 22 members of the kindred of a 24-year-old woman with hypophosphatasia. We measured activity of AP in serum and leukocytes, and the urinary excretion of PPi and PEA. Within this kindred, urinary excretion of PPi appeared to indicate carrier status, and among the clinically normal adults, values for this analyte were inversely correlated with the activity of AP in serum. These results suggest that urinary excretion of PPi is sensitive to subtle changes in the activity of AP.

Adolescent↗
PubMed1988

Erythrocyte phosphate metabolism and pH in vitro: a model for clinical phosphate disorders in acidosis and alkalosis.

When whole blood from 9 normal donors was incubated at 37 degrees C for 90 min under 95%, O2/5% CO2, over a range of pH from 7.1 to 7.9, the concentrations of orthophosphate (Pi) in plasma, in whole blood and in the cells decreased with increasing pH. At all pHs the ratio of cell to plasma concentrations of Pi was higher than that predicted from the cell to plasma distribution ratio for chloride, on the assumption that the mono- and di-anionic forms of Pi distributed passively in response to the membrane potential. Both the observed and predicted distribution ratios for Pi, and the difference between them, decreased with increasing pH. It is concluded that the observed distribution of Pi between erythrocytes and plasma is not consistent with a steady-state passive distribution, and that small changes of pH in vitro can lead to marked alterations in cellular Pi concentration. These measurements provide a direct example of the redistribution of Pi between cells and plasma, which has been postulated to occur in glycolyzing cells, leading to Pi depletion, during pH disturbances in vivo.

2,3-Diphosphoglycerate↗
PubMed1988

Prevalence of Campylobacter in infant, juvenile and adult laboratory primates.

A cross-sectional study of Campylobacter spp. infection was conducted on 125 infant (Macaca nemestrina and Macaca fascicularis) in an infant primate nursery housing infants from birth to 18 months of age, and 145 M. nemestrina aged from 4 months to 15 years at another facility (Primate Field Station) housing animals from birth to aged adults. The objective was to determine the prevalence of Campylobacter spp. in various age groups and to investigate the correlation with diarrhea. In the Infant Primate Research Laboratory approximately 70% of infants were infected at 18 months-old. Campylobacter coli was isolated from approximately two-thirds of the infected infants. One-third were Campylobacter jejuni and occasional infants were infected with a naladixic acid resistant, hippurate negative (NAR) Campylobacter spp. At the Primate Field Station virtually all animals cultured in 4-6 month-old, 16-20 month-old, and 3-5 year-old age groups were positive. Approximately one-third of middle-aged adults (10-15 years old) were positive with C. coli or NAR Campylobacter spp. Environmental factors such as location and movement of animals may provide an explanation for the prevalence data obtained in the two facilities and different age groups of animals. An etiologic role of Campylobacter spp. in diarrhea of laboratory primates was not established in this study.

Age Factors↗
PubMed1987

Interleukin 1 preferentially stimulates the production of tissue-type plasminogen activator by human articular chondrocytes.

Interleukin 1, derived from human placenta, stimulates plasminogen activator activity in human articular chondrocytes. The stimulation of plasminogen activator activity can be abolished by preincubation of placental interleukin 1 with an antiserum to homogeneous 22K factor, a species of interleukin 1 beta, indicating that the stimulation of plasminogen activator activity is due to interleukin 1 and not contaminating factors. Chondrocytes produce three species of plasminogen activator, with apparent Mr approximately 50,000, 65,000 and 100,000 as determined after sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis with gels containing casein and plasminogen. Both placental interleukin 1 and 22K factor enhance the production of the species of Mr approximately 65,000 and 100,000. Comparison of the mobility of the plasminogen activator species on SDS-polyacrylamide gel electrophoresis with human urokinase (u-PA) and human melanoma tissue-type plasminogen activator (t-PA) and studies with antibodies to these enzymes indicate that the Mr approximately 50,000 species is a u-PA and the Mr approximately 65,000 a t-PA. The Mr approximately 100,000 species is possibly an enzyme-inhibitor complex. Interleukin 1 therefore appears to enhance the production of t-PA and a putative enzyme-inhibitor complex. Abolition of plasminogen activator activity in the fibrin plate assay with antibodies to t-PA and u-PA also confirms enhanced t-PA production on interleukin 1 stimulation, though there is also evidence for increased cell-associated production of u-PA.

Cartilage, Articular↗
PubMed1987

Nucleoside triphosphate pyrophosphatase of rabbit matrix vesicles, a mechanism for the generation of inorganic pyrophosphate in epiphyseal cartilage.

Inorganic pyrophosphate (PPi) may be important in the regulation of mineralisation but its origin in epiphyseal cartilage is ill-defined. Nucleoside triphosphate pyrophosphatase is one potential source, as this enzyme catalyses the formation of PPi from nucleoside triphosphates. This enzyme has been identified in matrix vesicles derived from rabbit epiphyseal cartilage and a method developed to measure the activity using ATP as substrate in intact matrix vesicles under relatively physiological conditions. The enzyme had a high affinity for ATP (Km less than 10 microM) and was also active towards GTP, CTP and UTP. Disruption of the matrix vesicle membrane by sonication failed to alter the activity. Treatment of sonicated matrix vesicles with Triton X-100 increased the activity which may indicate a direct effect of the detergent on the enzyme. Activity towards ATP was inhibited substantially by ADP and AMP and by another potential substrate beta,gamma-methyleneadenosine 5'-triphosphate. Dichloromethylene bisphosphonate, an analogue of the product PPi, inhibited the activity to a lesser extent. Two other potential substrates, NADP+ and thymidine 5'-monophosphate p-nitrophenyl ester were only weakly inhibitory as was 1-hydroxyethylidene 1,1-bisphosphonate. These results imply that nucleoside triphosphates are the substrates in vivo and the inhibitory effects of ADP and AMP suggest mechanisms whereby this activity could be regulated.

Animals↗