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Biomedical subjects

R G Russell

Publications and source records attributed to R G Russell.

At least 199 records · Page 11Linked to original sources
PubMed1986

Vitamin D metabolites in patients with established non-union of fracture.

The serum concentrations of vitamin D metabolites and biochemical markers of bone metabolism were measured in 15 patients with established non-union of fracture and in 15 age- and sex-matched controls. No significant differences between the two groups were observed in the concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3; or in the biochemical indices of skeletal metabolism. These results suggest that patients with established non-union have normal bone turnover with no evidence of disturbed production or utilization of 24,25-dihydroxyvitamin D3 or other major vitamin D metabolites. Disturbances in vitamin D metabolism are unlikely therefore to make a major contribution to the maintenance of non-union of fracture.

24,25-Dihydroxyvitamin D 3↗
PubMed1985

Identification of ecto-nucleoside triphosphate pyrophosphatase in human articular chondrocytes in monolayer culture.

In cultured monolayers of human articular chondrocytes we have observed an enzyme activity which catalyzes the extracellular conversion of ATP to AMP and PPi. The enzyme was active at very low concentrations of ATP (microM) and exhibited optimal activity at concentrations of ATP of approx. 100 microM. The enzyme was active in intact cells as judged by measurement of the release of the cytoplasmic marker enzyme lactate dehydrogenase. No increase in production of PPi from ATP was observed on mechanically disrupting the cells and no activity was shed into the medium by intact cells. Activity was stable between days 4 and 8 after subculturing the cells and was not affected by the timing of the final medium change prior to assay. Activity was also observed with other nucleoside triphosphates (GTP, CTP and UTP). We suggest that this activity is attributable to ecto-nucleoside triphosphate pyrophosphatase. This observation may be important in relation to the pathogenesis of the human disease of chondrocalcinosis in which crystals of calcium pyrophosphate dihydrate deposit in articular cartilage.

Adenosine Triphosphate↗
PubMed1985

Intravenous clodronate in the treatment and retreatment of Paget's disease of bone.

The effects of short courses (5 days) of intravenous clodronate 300 mg daily were studied in 31 patients with active Paget's disease of bone. The diphosphonate induced a striking reduction in biochemical indices of disease activity, which was sustained for at least 6 months after withdrawal of treatment. Apparent resistance to further treatment in patients previously treated for Paget's disease was an artefact due to incomplete relapse before retreatment. There was no significant difference in the degree of suppression of alkaline phosphatase activity between patients given intravenous clodronate and 45 patients given clodronate 1.6 g daily by mouth for 6 months. Short-term intravenous clodronate provides a useful alternative strategy for the treatment of patients with Paget's disease.

Administration, Oral↗
PubMed1985

Retinoids and synovial factor(s) stimulate the production of plasminogen activator by cultured human chondrocytes. A possible role for plasminogen activator in the resorption of cartilage in vitro.

Agents such as retinol, interleukin 1 and catabolin stimulate resorption of cultured cartilage. This process seems to be mediated by chondrocytes, but the mechanism by which breakdown occurs remains unknown. We have found that (10(-6)-10(-8) M) retinoic acid and (1 X 10(-6) M) retinol, in the presence or absence of a factor derived from cultured synovium (synovial factor), stimulate the degradation of fibrin by human chondrocytes in culture. Plasminogen was required for the enhancement of fibrinolysis, suggesting that the breakdown depended upon the production of plasminogen activators and subsequent liberation of plasmin. However, the chondrocytes did not release significant amounts of plasminogen activator, and the effects of the synovial factor and retinoids resulted from augmentation of the production or activity of enzymes which remained bound to the cell layer. The role of plasminogen in the resorption of cultured cartilage was also investigated. In the presence of plasminogen, (1 X 10(-8) M) retinoic acid or synovial factor stimulated the breakdown of cultured bovine nasal cartilage, but in the absence of plasminogen, the effect of synovial factor was abolished and that of retinoic acid reduced. However, in cultures containing both retinoic acid and synovial factor the resorption process was not affected by removal of plasminogen. Thus, the resorption of cartilage matrix in vitro may be partially mediated by plasminogen activators and plasmin.

Animals↗
PubMed1985

Partial purification of a factor from human synovium that possesses interleukin 1, chondrocyte stimulating and catabolin-like activities.

Human synovial explants in culture release material that stimulates the production of prostaglandin E2 (PGE2) and several extracellular enzymes by human chondrocytes. Fractionation of conditioned medium by gel filtration revealed a protein of approx. 15 kDa, which in addition to stimulating production of PGE2 and plasminogen activator by human articular chondrocytes, possessed interleukin 1 activity and induced cartilage degradation. Further purification using iso-electric focussing again showed co-elution of these activities with a major pI of 6.9 and a minor pI of 5.1-5.3. This study indicated that human synovium releases a factor that is closely related to or identical with interleukin 1 and suggests that this protein may participate in cellular interactions that occur within the rheumatoid joint.

Animals↗
PubMed1985

Modulation of connective tissue metabolism by partially purified human interleukin 1.

We have investigated the relationship between the monokine interleukin 1 (IL-1) and the connective tissue-stimulating activities produced by monocytes such as mononuclear cell factor (MCF). Using almost exclusively human tissue we have monitored a wide range of MCF-like activities through the partial purification of IL-1 by gel filtration and isoelectric focusing. Activities measured include stimulation of chondrocytes to produce prostaglandins, plasminogen activator and proteoglycanase, enhancement of synovial cell proliferation, and stimulation of cartilage resorption, in addition to IL-1 (lymphocyte activating factor) activity. The activities described show the same molecular heterogeneity; the active material has similar potencies in the different systems, and removal of IL-1 activity by pretreatment with phenylglyoxal also results in loss of the connective tissue-stimulating activities. These results show that the factors responsible for this wide range of activities are very closely related to IL-1 and give further evidence in support of the possible involvement of IL-1 in the processes of joint destruction occurring in chronic inflammatory conditions such as rheumatoid arthritis.

Connective Tissue↗
PubMed1985

Comparative effects of an antiviral drug, inosiplex, and diphosphonates in Paget's disease of bone.

The effects of the antiviral agent, inosiplex, were assessed in four patients with Paget's disease of bone. Treatment for 6 months did not suppress disease activity as judged by serum alkaline phosphatase and hydroxyprolinuria, and viral inclusions persisted in the one patient from whom a bone biopsy was taken. These results contrasted markedly with the suppressive effects of diphosphonate treatment in these same patients.

Alkaline Phosphatase↗
PubMed1985

Treatment of malignant hypercalcaemia with clodronate.

We have assessed the effects of clodronate (dichloromethylene diphosphonate; Cl2MDP 0.8-3.2g daily by mouth for up to 3 months) in 17 episodes of hypercalcaemia and osteolysis due to carcinoma. Clodronate reduced serum calcium in 14 episodes and bone resorption in all patients. These remained suppressed for the duration of treatment, but recurred promptly when treatment was stopped. Clodronate may be a useful measure for controlling hypercalcaemia and osteolysis in patients with carcinoma.

Adult↗
PubMed1985

Effects of dietary fish oil supplementation on the fatty acid composition of the human platelet membrane: demonstration of selectivity in the incorporation of eicosapentaenoic acid into membrane phospholipid pools.

The fatty acid composition of membrane phospholipids of stimulated and unstimulated platelets was studied in six normal volunteers given a daily dietary supplement of a fish oil rich in eicosapentaenoic acid (EPA) for 4 weeks. The supplement was equivalent to 1.8 g of EPA daily. Thromboxane synthesis and platelet aggregation responses to sodium arachidonate, thrombin and the ionophore A23187 were also investigated. A marked increase in the relative EPA content of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was noted after 2 and 4 weeks fish oil supplementation. However, there was no incorporation into phosphatidylinositol (PI) or phosphatidylserine (PS). The relative arachidonic acid (AA) content of PC and PE was significantly reduced at 2 and 4 weeks but that of PI and PS remained unchanged. Significant reductions in the relative linoleic acid content of total phospholipids, PC and PE were also noted. Stimulation of platelets obtained after 4 weeks fish oil supplementation by thrombin and A23187 was associated with a marked reduction in the AA content of PI and a minor reduction in that of PE. There was no change in the relative proportions of EPA in PI, PS, PC or PE after stimulation. Throughout the study there were no significant changes in platelet aggregation responses or in platelet thromboxane production. Our results indicate that the incorporation of EPA into the platelet membrane phospholipids is selective and that if PI is the major source of AA for platelet prostaglandin biosynthesis then the reported beneficial effects of EPA on haemostasis cannot be explained on the basis of its incorporation into and mobilization from the platelet membrane phospholipid pool.

Adult↗
PubMed1985

A technique for the measurement of orthophosphate in human erythrocytes, and some studies of its determinants.

A technique is described for the determination of orthophosphate (Pi) in human erythrocytes. The advantages of the technique are that it uses whole blood rather than separated erythrocytes, that it avoids major hydrolysis of organic phosphates, that it takes account of incomplete recovery of Pi and that it minimizes the effects of chilling the cells. In chilled samples from 46 patients in an intensive care unit, the cellular concentration of Pi was proportional to that in plasma. Blood samples from nine normal subjects were incubated at 37 degrees C. The cellular Pi was 0.79 mmol/litre of cells using an external standardization and 0.67 using an internal standardization. When the same cell samples were chilled on ice for 30 min, the internally standardized value decreased further to 0.57 mmol/litre of cells. These results suggest that differences in recovery, and the extent of chilling, contribute to the variability in the previously reported values for erythrocyte Pi. If Pi, like chloride, had distributed passively between cells and plasma in these samples, the cell to plasma molar concentration ratio for Pi should have been 0.29, compared with the measured value of 0.64. This difference suggests that some factor, in addition to passive diffusion, determined the distribution of Pi.

Cold Temperature↗
PubMed1985

Phosphate metabolism in erythrocytes of critically ill patients.

Orthophosphate (Pi), adenosine 5'-diphosphate (ADP), adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) were measured in the erythrocytes of patients in an intensive care unit. The patients' plasma concentration of Pi varied from 0.1 to 4.2 mmol/l, and the corresponding concentration in erythrocytes varied from 0.1 to 2.0 mmol/litre of cells. Marked ATP depletion (less than 1 mmol/litre of cells) was only observed when erythrocyte Pi was less than 0.3 mmol/litre of cells and plasma Pi was less than 0.35 mmol/l. No dependence of 2,3-DPG concentration on the cellular concentration of Pi was detected. The phosphorylation potential [ATP]/([ADP] X [Pi]) varied inversely with the erythrocyte concentration of Pi. Hence the calculated free energy of hydrolysis of ATP in the cell increased from -58 kJ/mol in the most hypophosphataemic samples to -51 kJ/mol in the most hyperphosphataemic. Such changes may adversely affect cell function by altering the steady state mass-action ratios of ATPase reactions. When erythrocytes from normal donors were incubated in solutions containing 1 or 5 mmol/l Pi, the cellular concentrations of Pi stabilized at 1.09 and 2.85 mmol/litre of cells respectively. The corresponding rates of lactate production were 2.09 and 3.11 mmol h-1 litre-1 of cells. In spite of this stimulation of glycolysis (and hence of the flux through ATP synthesizing steps of the Embden-Meyerhof pathway), no significant change in ATP concentration was observed. As in the patients' cells, this indicates that, when extracellular Pi concentrations are perturbed, the concentrations, in erythrocytes, of organic phosphates are more closely regulated than the concentration of Pi.

2,3-Diphosphoglycerate↗
PubMed1985

Abnormal vitamin D metabolism in Paget's disease of bone.

We have studied several biochemical indices of bone turnover and vitamin D metabolism in 32 untreated patients with Paget's disease and in 32 age-matched control subjects. patients with Paget's disease, as expected, were characterized by high bone turnover, as judged by alkaline phosphatase and urinary excretion of hydorxyproline. Serum values of 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and the ratio of 24,25(OH)2D3 to 25-OHD were significantly lower in patients than in control subjects. Serum concentrations of 1,25(OH)2D3 were normal in Paget's disease. The distribution of values for 24,25(OH)2D3 was log normal. On the basis of the normal range computed from control subjects, patients were divided into those with low or normal values for 24,25(OH)2D3. Disease activity, as judged by biochemical indices was significantly higher in the patients with the lower values of 24,25(OH)2D3. We conclude that Paget's disease is characterized by low circulating concentrations of 24,25(OH)2D3, particularly in patients with more extensive or severe disease.

24,25-Dihydroxyvitamin D 3↗
PubMed1985

Stimulation of the proliferation of human bone cells in vitro by human monocyte products with interleukin-1 activity.

The process of induction of bone formation, which follows bone resorption during normal and pathological bone turnover, is well documented. However, the mechanisms responsible for this process are unclear. Mononuclear phagocytes present at the sites of bone remodeling could play a role in this "coupling" of bone formation to bone resorption. This study was designed to investigate such a possibility. By measuring both the increase in [3H]thymidine incorporation and in cell number, we found that human monocytes in culture released factors capable of stimulating the proliferation of osteoblast-like cells derived from human bone. Rapidly dividing cells exhibited a greater response to interleukin 1 (IL-1) than confluent cells. The factors are similar to IL-1 in that they exhibited the same molecular weight and isoelectric point, were present in fractions that contained IL-1 activity after gel filtration chromatography and isoelectric focusing, and showed similar dose-response characteristics. Proliferation was more marked when prostaglandin production by the cells, which was also stimulated by these factors, was inhibited by indomethacin. A factor produced by monocytes that affects osteoblast activity may be important in the coupling of osteoclast and osteoblast actions.

Bone and Bones↗
PubMed1985

Variability in limb malformations and possible significance in the pathogenesis of an inherited congenital neuromuscular disease of Charolais cattle (syndrome of arthrogryposis and palatoschisis).

Limb abnormalities in 30 calves with an inherited congenital neuromuscular disorder known as syndrome of arthrogryposis and palatoschisis were classified according to the range of severity of joint deformity in either flexion or extension, and restricted joint movement. Joint movement was variably affected; it was either normal, lax, restricted in the range of mobility, or occasionally, fixed. The characteristic findings were: bilateral hyperextension of the hind fetlock, flexion deformity of the forelimb that particularly involved the fetlock and the carpus, with restricted articular movement and complete rigidity in some cases. One-third of calves also had medial deviation of the forelimb due to angular deformity of articular surfaces in the carpus. All nine live calves were floppy due to marked generalized muscular hypotonia. Birth weight of deformed calves was reduced. In some calves muscle development was impaired as judged by muscle weight, and histological examination. In some calves the gross appearance, muscle weight and histological examination revealed no abnormal development and indicated that the effects on skeletal muscle were secondary. No lesions were found in the spinal cord of 23 of 24 calves examined histologically. The remaining calf had a localized cavitation in the dorsal white matter at T2-3. Based on the observations in calves in this study it is proposed that both primary and secondary factors contribute to the phenotypic expression of this congenital deformity. The primary lesion is considered to be a neurogenic abnormality of differentiation in the central nervous system. Cytogenetic analysis of 16 carrier cows and two deformed calves showed normal karyotypes. Serology for Akabane virus in 16 carrier cows was negative.

Abnormalities, Multiple↗
PubMed1985

Vitamin D metabolites regulate osteocalcin synthesis and proliferation of human bone cells in vitro.

The effects of six natural vitamin D metabolites of potential biological and therapeutic interest, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), 25-hydroxyvitamin D3 (25-OH-D3), 24R,25-dihydroxyvitamin D3 (24R,25-(OH)2D3), 1,24R,25-trihydroxyvitamin D3 (1,24R,25-(OH)3D3), 25S,26-dihydroxyvitamin D3 (25S,26-(OH)2D3) and 1,25S,26-trihydroxyvitamin D3 (1,25S,26-(OH)3D3) on cell replication and expression of the osteoblastic phenotype in terms of osteocalcin production were examined in cultured human bone cells. At a dose of 5 X 10(-12) mol/1, 1,25-(OH)2D3 stimulated cell proliferation, whereas at higher doses (5 X 10(-9)-5 X 10(-6) mol/1) cell growth was inhibited in a dose-dependent manner. The same pattern of effects was seen for the other metabolites in a rank order of potency: 1,25-(OH)2D3 greater than 1,25S,26-(OH)3D3 = 1,24R,25-(OH)3D3 greater than 25S,26-(OH)2D3 = 24R,25-(OH)2D3 = 25-OH-D3. Synthesis of osteocalcin was induced by 1,25-(OH)2D3 in doses similar to those required to inhibit cell proliferation. Biphasic responses were observed for some of the metabolites in terms of osteocalcin synthesis, inhibitory effects becoming apparent at 5 X 10(-6) mol/1. The cells did not secrete osteocalcin spontaneously. These results indicate that vitamin D metabolites may regulate growth and expression of differentiated functions of normal human osteoblasts.

24,25-Dihydroxyvitamin D 3↗
PubMed1984

The effects of monocyte-conditioned medium and interleukin 1 on the synthesis of collagenous and non-collagenous proteins by mouse bone and human bone cells in vitro.

Cultured adherent human mononuclear cells produce factor(s) which stimulate the release of calcium from new-born mouse calvaria in organ culture. This stimulation of bone resorption is accompanied by an inhibition of the incorporation of [3H]proline into collagen which is independent of increased prostaglandin production by the bone. When human osteoblast-like cells are treated with conditioned medium from human mononuclear cells, collagen accounts for a decreased proportion of the protein synthesised. This effect on matrix synthesis is not accompanied by an inhibitory action of the monocyte-conditioned medium preparations on net cell proliferation. In human osteoblast-like cell cultures, partially purified human interleukin 1 also inhibits the production of the bone-specific protein osteocalcin in a dose-dependent fashion. These observations are consistent with the hypothesis that products of human monocytes similar to, or identical with, human interleukin 1 may be important regulators of bone metabolism and may contribute to the bone loss seen in diseases such as chronic rheumatoid arthritis.

Animals↗