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D R Blake

Publications and source records attributed to D R Blake.

At least 253 records · Page 14Linked to original sources
PubMed1986

Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study.

A detailed ultrastructural study was made of the synovial iron deposits in cases of haemophilic synovitis (HS), pigmented villonodular synovitis (PVNS), rheumatoid arthritis (RA), osteoarthritis (OA), seronegative inflammatory arthritis (SNA), and in controls, to investigate the relationship between iron deposits and tissue damage. Iron was seen by electron microscopy in about 75% of synovial lining cells in HS and PVNS but only in about 25% of synovial cells from cases of RA and SNA. In cases of OA and in controls iron deposits were scarce. The iron was usually deposited within pleomorphic siderosomes and in HS was most common in type A synovial cells. In contrast, deposits in all other cases were more common in type B cells, which were frequently the predominant cell type, and siderosomes were smaller, more homogeneous, and were more common in deeper synovial tissue. Considerable tissue damage was noted in the vicinity of iron rich siderosomes in synovial A cells from cases of HS, but such deposits in B cells in the synovium from the other cases had relatively little effect. We discuss the possibility that such differences directly reflect the differing functions of type A and B synovial cells, and particularly their relative ability to produce metabolically active oxygen metabolites with tissue destructive potential in the presence of iron.

Arthritis↗
PubMed1986

Is chronic synovitis an example of reperfusion injury?

In an attempt to define why the joint synovial cavity is prone to develop persistent synovial inflammation we show that hypoxia is induced by pressure changes caused by exercise in the presence of an inflammatory effusion. On resting 'reperfusion injury' may take place. The biochemistry of reperfusion injury has only recently been defined and perhaps surprisingly for an insult that has hypoxia as its central ingredient involves the subsequent production of oxygen derived free radical species. We apply the reaction sequences that are believed to occur during hypoxic/reperfusion injury to the joint synovial cavity and, on the basis of reported 'in vivo' observations, suggest novel therapeutic approaches that we believe are applicable to the treatment of persistent synovial inflammation.

Animals↗
PubMed1986

Neutropenia in patients with inflammatory arthritis treated with sulphasalazine.

This report describes two patients who developed severe neutropenia one month after starting sulphasalazine (SASP) as treatment for their inflammatory joint disease. Both recovered on stopping the drug. Six further cases (out of a series of 180 patients with inflammatory forms of arthritis receiving SASP therapy) in whom transient leucopenia occurred are also recorded. These patients were able to continue the drug under close supervision. Sulphasalazine is a useful addition to the small number of slow acting antirheumatic drugs (SAARDs) and, despite this complication, is safer than other SAARDs. Careful monitoring of patients is essential, however, particularly in the early stages of treatment, to detect this adverse reversible reaction promptly.

Acute Disease↗
PubMed1985

The behaviour of caeruloplasmin in stored human extracellular fluids in relation to ferroxidase II activity, lipid peroxidation and phenanthroline-detectable copper.

No Cu(II) ion is measurable in human serum or synovial fluid by the phenanthroline assay. On storage of human serum or synovial fluid at 4 degrees C, phenanthroline-detectable copper appears, lipid peroxidation occurs, ferroxidase I activity declines and ferroxidase II activity rises, yet there is no fall in immunologically detectable caeruloplasmin. Storage of body fluids at -20 degrees C or -70 degrees C slows, but does not prevent, these deteriorative changes. It is suggested that the presence of low-molecular-mass Cu(II) ion complexes, ferroxidase II activity, "cytotoxic factors' and "immunosuppressive factors' in body fluids may be, in part or in whole, an artifact of the storage and handling of the fluids. A report [Blake, Blann, Bacon, Farr, Gutteridge & Halliwell (1983) Clin. Sci. 64, 551-553] that the caeruloplasmin present in rheumatoid synovial fluid is deficient in ferroxidase activity is shown to be such an artifact. It is strongly recommended that all such experiments be performed upon freshly taken fluid samples.

Arthritis, Rheumatoid↗
PubMed1985

Human parvovirus arthropathy.

19 of 153 patients attending an early-synovitis clinic were shown to have been recently infected by the human parvovirus (HPV). 5 other patients had evidence of some other closely preceding infection. HPV-infected patients typically presented with symmetrical peripheral polyarthropathy of sudden onset and moderate severity. Usually there was some improvement within 2 weeks, but in 17 patients symptoms persisted for more than 2 months, and in 3 for more than 4 years. Arthropathy in the absence of the facial rash that characterises HPV infection in children is a common presentation of the infection in adults.

Adolescent↗
PubMed1985

Immunohistochemical findings in rheumatoid nodules.

Eighteen nodules from patients with rheumatoid disease were studied histologically and immunohistochemically. A continuum of microscopic changes was observed with varying degrees of fibrinoid necrosis, mononuclear cell infiltration and healing by fibrous scarring. In two cases there was focal evidence of arteritis. Fibrin was plentiful in the necrotic areas of nodules. Small amounts of immunoglobulin were identified in plasma cells and as irregular extracellular deposits in and around areas of necrosis. In a single small vein abnormal IgG was detected. Mononuclear cells surrounding areas of necrosis stained strongly with antisera to ferritin and a cytoplasmic macrophage antigen, stained variably with muramidase (lysozyme) and negatively with alpha-1 antitrypsin antibodies. Perls' stain for ferric iron was almost entirely negative and ultrastructural x-ray microanalysis indicated that the cytoplasm of these cells were entirely free of iron. These findings confirm the chronic inflammatory nature of rheumatoid nodules but provide no support for the view that they originate in areas of vasculitis. A relative lack of cytoplasmic antiprotease along with a strong expression of ferritin appears to be a characteristic feature of macrophages in rheumatoid tissue.

Adult↗
PubMed1985

Endothelial cell cytotoxicity in inflammatory vascular diseases--the possible role of oxidised lipoproteins.

One of the proposed mechanisms of vascular damage in connective tissue disease is the direct action of a cytotoxic serum factor inducing endothelial cell damage. The nature of this serum factor is unclear, but has been suggested to be a lipoprotein. Sera from patients with (1) systemic necrotising arteritis (polyarteritis nodosa, Wegener's granulomatosis, and necrotising arteritis associated with rheumatoid synovitis), (2) systemic or joint restricted rheumatoid disease, and (3) large vessel/giant cell arteritis have been examined for cytotoxicity to human cultured endothelial cells and azide-resistant ferroxidase-like activity (indicative of the oxidised lipoprotein content). Stored sera from patients with necrotising arteritis showed a significantly enhanced tendency to develop oxidised lipoprotein, which correlated closely with human endothelial cell cytotoxicity. Fresh sera also contained this factor, but to a lesser extent. It is argued that the cytotoxic factor detected in previous clinical studies is in part an in-vitro artefact, although its accelerated development in certain patient groups might suggest an excess of pro-oxidants that have developed in vivo.

Arteritis↗
PubMed1985

Effect of intravenous iron dextran on rheumatoid synovitis.

Eleven patients with rheumatoid arthritis received a total dose infusion of iron dextran for anaemia. Two of them had anaphylactic reactions and the remaining nine an exacerbation of synovitis. Quantitative infrared thermal imaging was used to assess the extent and distribution of joint involvement resulting from this therapy. In all eight patients examined the 'thermographic index' increased in two or more joint areas, indicating an increase in inflammation. Small joints of the hands were maximally affected, though larger joints when previously inflamed also worsened. Uninflamed joints were rarely affected. The exacerbation of synovitis occurred 24-48 h after completion of the iron dextran infusion and corresponded with a saturating of the serum iron binding capacity. Levels of immune complexes were unaltered, implying normal reticuloendothelial function. In one further patient, reported to have synovial flares when challenged with oral ferrous sulphate, iron dextran was infused at a lower dosage. All previously inflamed joints in this patient worsened 12 h after the infusion was discontinued. Concomitant with this was an increase of lipid peroxidation products in synovial fluid and to a less extent serum. Iron dextran in vitro stimulated lipid peroxidation, but dextran alone had no effect. It is therefore suggested that iron dextran worsens synovial inflammation by promoting lipid peroxidation.

Adult↗
PubMed1985

Effect of blood on the activity and persistence of antigen induced inflammation in the rat air pouch.

The hypothesis that haem iron derived from synovial microbleeding has a proinflammatory effect on the synovial membrane was tested by adding autologous whole blood and fractions derived from it to a naturally remitting rat air pouch model of allergic inflammation. The induction of such a subcutaneous air pouch produces a cavity lined by mesenchymal cells comparable to the synovial membrane. Autologous whole blood was found to prolong a low grade inflammatory state, this effect being attributable to a red cell component, most probably haem iron. Whole blood in the absence of an inflammatory stimulus does not have this effect, indicating that the mechanism is one of prolonging or promoting existing allergic inflammation, rather than inducing an inflammatory response.

Air↗
PubMed1985

Self-perpetuating mechanisms of immunoglobulin G aggregation in rheumatoid inflammation.

When human IgG is exposed to free radical generating systems such as ultraviolet irradiation, peroxidizing lipids, or activated human neutrophils, characteristic auto-fluorescent monomeric and polymeric IgG is formed (excitation [Ex], 360 nm, emission [Em], 454 nm). 1 h ultraviolet irradiation of IgG results in the following reductions in constituent amino acids; cysteine (37.0%), tryptophan (17.0%), tyrosine (10.5%), and lysine (3.6%). The fluorescent IgG complexes, when produced in vitro, can stimulate the release of superoxide from normal human neutrophils. In the presence of excess unaltered IgG, further fluorescent damage to IgG occurs. Measurement and isolation of fluorescent monomeric and polymeric IgG by high performance liquid chromatography, from in vitro systems and from fresh rheumatoid sera and synovial fluid, indicates that identical complexes are present in vivo; all these fluorescent complexes share the property of enhancing free radical production from neutrophils. The results described in this study support the hypothesis that fluorescent monomeric and aggregated IgG may be formed in vivo by oxygen-centered free radicals derived from neutrophils, and that in rheumatoid inflammation this reaction may be self-perpetuating within the inflamed joint.

Adult↗
PubMed1985

Audit of closed synovial biopsy in the diagnosis of inflammatory joint disease.

In a prospective study, the clinical features and synovial histopathology of 78 patients with joint disease were compared. Nineteen patients had early rheumatoid disease, 19 chronic rheumatoid, 17 chondrocalcinosis or osteoarthritis, 10 persistent monoarthritis and 14 other miscellaneous arthropathies. After semiquantitative assessment of the degree of inflammatory infiltration, increase in vascularity, synovial hypertrophy and ulceration and fibrin deposition biopsies were categorized as either normal, or slightly or severely abnormal. The highest incidence of severely abnormal biopsy was in patients with chronic rheumatoid disease and miscellaneous forms of arthritis. Major histological abnormalities were uncommon in osteoarthritis, chondrocalcinosis and persistent monoarthritis. Generally, histology was of little help in differential diagnosis, but in early rheumatoid disease there was a relationship between the clinical degree of knee joint disease and the category of histological change. In these patients, general disease activity was reassessed at least 18 months after biopsy. All those with severely abnormal biopsies had persistent or severe persistent rheumatoid disease, whereas 3 of the 4 patients with normal biopsies had no evidence of active synovitis.

Arthritis↗
PubMed1985

The determination of dehydroascorbic acid and ascorbic acid in the serum and synovial fluid of patients with rheumatoid arthritis (RA).

Using a novel high performance liquid chromatography (HPLC) determination of ascorbic acid and dehydroascorbic acid, we have measured the relative amounts of ascorbate and dehydroascorbate in 20 normal controls and in paired sera and synovial fluid from 13 patients with rheumatoid arthritis (RA). In complete contrast to previous published findings we were able to detect dehydroascorbate in normal human sera (12.0 +/- 3.7 mumol/l), while the mean and range of ascorbate measured in normals was 69.6 +/- 20.6 mumol/l. These findings were completely reversed in rheumatoid sera (21.8 +/- 8.6 mumol/l and 5.1 +/- 5.0 mumol/l for dehydroascorbate and ascorbic acid respectively). In several rheumatoid sera no ascorbate could be detected. In paired synovial fluid and serum samples, there was always more dehydroascorbate detected in synovial fluids than in the corresponding sera (p less than 0.01). The data suggests that the reduced level of ascorbate and increased level of dehydroascorbate may be a reflection of the increased antioxidant and free-radical scavenging activity of the vitamin in RA, especially within the inflamed joint.

Adult↗
PubMed1985

A possible role for ferritin during inflammation.

Inflammation induces the hepatic synthesis of the iron storage protein (apo)ferritin, which is released into the circulation, and behaves as an acute phase protein. The biological significance of the extracellular rise in serum (apo)ferritin is unknown. We have observed that (apo)ferritin will stimulate superoxide production from neutrophils in the presence of cytochalasin B across a physiologically appropriate concentration range. We therefore propose that extracellular ferritin has an important role in host defence against bacteraemia by stimulating oxidative metabolism.

Animals↗
PubMed1985

Cerebral and ocular toxicity induced by desferrioxamine.

Seven patients with rheumatoid disease were given the iron-chelating drug desferrioxamine (DFX) to evaluate its possible anti-inflammatory effects. Two of these patients, who also received the anti-emetic prochlorperazine, lost consciousness for 48-72 h and then fully recovered. Electroencephalography showed abnormalities of the type associated with metabolic disturbance. One of these patients showed pyramidal features and subsequently developed an optic neuropathy and pigmentary retinopathy. Analysis of his cerebrospinal fluid showed a decrease in loosely-bound (catalytic) iron and increase in loosely-bound (catalytic) copper, total iron and products of lipid peroxidation, with values approaching normal as the symptoms resolved. Subsequent in vivo/vitro studies clearly demonstrated that the neurological effects were due to a synergistic action of desferrioxamine and prochlorperazine, probably resulting in exceptional fluxes of intra/extra cellular iron/copper disturbing noradrenergic and serotonergic systems. Two other patients who did not receive prochlorperazine, developed retinal problems which later improved, one after only 15 g of desferrioxamine. Our observations suggest a new model for metabolic encephalopathy studies and provide insight into the mechanisms of pigmentary retinopathy.

Adult↗
PubMed1984

The effect of synovial iron on the progression of rheumatoid disease. A histologic assessment of patients with early rheumatoid synovitis.

Seventeen patients with early rheumatoid synovitis underwent synovial biopsy to assess the interrelationship between both ferritin (the intracellular iron storage protein) and Perls' positive iron (ferric iron in loose combination with protein), on the activity and course of rheumatoid disease. The amount of ferritin was associated to a significant degree with the activity of the disease at the time of biopsy, but showed no relation to the way the disease progressed over the following year. In contrast, the amount of Perls' iron bore no relation to the activity of the disease at biopsy, but its presence was associated with persistent disease. It is argued that this association is direct, that ferritin production may fail in a population of synovial macrophages, and that Perls' ferric iron may either be reduced to the ferrous form and promote the formation of toxic free radical species, or stimulate collagenase and prostaglandin release from synovial macrophages.

Arthritis, Rheumatoid↗