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Biomedical subjects

C G Winearls

Publications and source records attributed to C G Winearls.

At least 55 records · Page 3Linked to original sources
PubMed1990

Serum sickness and acute renal failure after streptokinase therapy for myocardial infarction.

A patient developed serum sickness and acute renal failure following therapy with streptokinase for myocardial ischaemia. There was a previous history of a cellulitic infection of the leg, and antibodies to streptokinase were measurable in a serum sample taken from the patient before therapy. A cryoglobulin was detected at the time of presentation with serum sickness. This contained polyclonal IgG (with anti-streptokinase activity), streptokinase, and C3. Circulating immune complexes were demonstrated by C1q-binding assay. Deposition of C3 was observed in skin and renal biopsies, and bound to erythrocytes. Renal histology, however, showed acute tubular necrosis, with no vasculitis or inflammatory cell infiltrate. This case provides an unusual example of the characterization of an immune complex comprising a specific antibody and an exogenous antigen, and has clinical implications for the use of streptokinase.

Acute Kidney Injury↗
PubMed1990

The quality of life of dialysis patients treated with recombinant human erythropoietin.

In June 1986, eight haemodialysis patients, seven male, one female, entered a pilot trial of recombinant human erythropoietin (EPO) at the Churchill Hospital Renal Unit. Six patients completed the Nottingham Health Profile (NHP) before starting EPO therapy, in order to assess quality of life, and were retested when haemoglobin level reached 120 g/l. A further test was given at one year. Statistically significant improvements were seen in the areas of Energy and Emotional Wellbeing. In the subsequent UK trial, involving previously transfusion dependent patients from nine centres, the pre and post treatment NHP scores of a further 18 patients have been assessed. Highly significant improvements were found in Energy, Physical Mobility (p less than 0.005) and in Emotional Wellbeing (p less than 0.002). Improvements which did not reach significance were found in the areas of Sleep, Social Isolation and Pain problems. An increase in appetite, and less sensitivity to cold were noted by over one third of patients. Problems with Employment, Looking after the Home, and Relationships were greatly reduced. We conclude that early findings show EPO treatment to improve not only the haemoglobin levels, but also the quality of life of haemodialysis patients with the anaemia of end stage renal failure.

Anemia↗
PubMed1989

Mechanism of immune complex-mediated damage: induction of interleukin 1 by immune complexes and synergy with interferon-gamma and tumor necrosis factor-alpha.

The ability of immune complexes derived from patients with type II mixed essential cryoglobulinemia to trigger the production of interleukin 1 (IL 1) was investigated. Immune complexes containing either IgM/IgG or IgA/IgG aggregates were shown to induce IL 1 production in human peripheral blood monocyte-enriched populations. Interferon-gamma alone did not induce detectable IL 1, but increased the IL 1 production induced by the immune complexes. Tumor necrosis factor-alpha, which is a potent inducer of IL 1, also enhanced IL 1 production following stimulation with suboptimal doses of the immune complex. The findings suggest that immune complexes may induce inflammation partly due to their capacity to induce the synthesis of IL 1.

Antigen-Antibody Complex↗
PubMed1989

Erythropoietin.

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Clinical Trials as Topic↗
PubMed1989

Treatment of anaemia in haemodialysis patients with recombinant erythropoietin.

Recombinant human erythropoietin (r-HuEPO) has been used for the treatment of renal anaemia in haemodialysed patients for more than 2 years. The recommended initial dose is 50 U/kg, intravenously, three times a week, subsequent to the dialysis procedure; if the increase in the haemoglobin level were insufficient after the 4-week therapy, the single doses should be elevated in steps of 25 U/kg each. A weekly total dose of about 200 U/kg (divided into 2 or 3 applications) will normally be adequate to stabilize the haemoglobin value at a level ranging between 10 and 12 g/dl. Patients on r-HuEPO require regular medical supervision, as--along with increasing haematocrit--hypertension and thrombosis of the arteriovenous fistula can develop. A slight increase in serum creatinine and potassium was observed in some of the studies.

Anemia↗
PubMed1989

Seizures in haemodialysis patients treated with recombinant human erythropoietin.

Administration of recombinant erythropoietin (r-HuEPO) is an effective treatment for the anaemia of chronic renal failure, but in some patients it has been accompanied by elevated blood pressure. This study focuses on seven patients with end-stage renal failure, managed on haemodialysis, who developed probable hypertensive encephalopathy with seizures during treatment with r-HuEPO. All made a full recovery. The events were not clearly related to the haemoglobin concentrations achieved, and four patients have subsequently been restarted on r-HuEPO therapy at a reduced dose, resulting in a slower increase in haemoglobin with no recurrence of episodes of severe hypertension. Close attention needs to be paid to blood pressure in patients commencing erythropoietin therapy, and it seems prudent to aim for a gradual increase in haemoglobin concentration to allow the circulation to adapt to changes in oxygen delivery and haematocrit.

Adult↗
PubMed1989

Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics.

Studies were directed to characterization of the anaemia of renal failure of 11 patients on haemodialysis and determination of the way in which it is corrected by human erythropoietin derived from recombinant DNA expressed in Chinese hamster ovary cells (r-HuEPO) administered intravenously. Erythrokinetics before treatment showed that total red cell mass was below normal and that both erythron transferrin uptake and red cell survival were modestly reduced; treatment increased both total red cell mass and erythron transferrin uptake but did not change red cell survival in previously untransfused patients. When BFU-e and CFU-e from patient bone marrow were cultured in autologous serum we found no evidence for inhibitors of erythroid progenitor maturation in patient serum compared with normal. Erythroid expansion in response to r-HuEPO was not limited by the availability of iron, iron requirements for new red cell formation being met from stores (if adequate) or from oral iron supplements. In pharmacokinetic studies the plasma clearance of r-HuEPO could be expressed by a three-parameter exponential curve with T1/2 range of 2.3 to 7.3 h. T1/2 after the first dose of r-HuEPO was not significantly different from that after 14 to 54 weeks treatment when the erythron had expanded to a new steady state. Erythron transferrin uptake before treatment was related to endogenous production of erythropoietin estimated from the plasma clearance of the first dose of r-HuEPO administered intravenously. This finding suggested that the availability of erythropoietin was the main factor limiting expansion of the erythron. This conclusion was supported by the continuity of the relationship during the response to treatment.

Adult↗
PubMed1988

Identification of glomerular immune deposits in cryoglobulinemia glomerulonephritis.

To provide further evidence of the nature of intraglomerular immune deposits in essential mixed cryoglobulinemia (EMC), we used two mouse monoclonal antibodies against cross-reactive idiotypes present on monoclonal rheumatoid factors (MoRFs) from patients with type II-EMC. MoAb Cc1 reacted with 9 of 16 circulating IgMk MoRFs tested, and MOAb Lc1 with four of the remaining. Using indirect immunofluorescence and immunoperoxidase techniques, we could identify the same cross-reactive idiotype of the serum MoRF in the renal biopsy specimens from 11 of 13 patients with EMC glomerulonephritis. Kidney specimens from the three patients, whose MoRF was not recognized by MoAbs Cc1 and Lc1, were negative. Two out of 30 control renal biopsies from patients with other forms of glomerulonephritis were shown to contain idiotype (Cc1 and Lc1) positive material. Both patients had serum polyclonal RF which could account for this finding. In conclusion, our results provide direct evidence that serum cryo-MoRF participate in the formation of glomerular immune deposits and, presumably, in the pathogenesis of renal damage in EMC glomerulonephritis.

Animals↗
PubMed1988

Erythroid progenitor cell kinetics in chronic haemodialysis patients responding to treatment with recombinant human erythropoietin.

The response of bone marrow and peripheral blood erythroid progenitors to human recombinant erythropoietin (rHuEPO) was studied in nine haemodialysed renal failure patients receiving this hormone for the correction of their anaemia. The haematocrit rose in all patients in response to thrice weekly injections of escalating rHuEPO doses (12-192 IU/kg). Both the numbers of CUF-e and BFU-e and their proliferative state in the bone marrow as well as BFU-e numbers in the peripheral blood were estimated before treatment and again after correction of the anaemia, at 16 h following an intravenous dose of rHuEPO. Following treatment bone marrow BFU-e numbers fell to a mean of 24.5% (P less than 0.01) of the pre-treatment values although there was no significant change in CFU-e or circulating BFU-e numbers. The mitotic rate (percentage S-phase cells) estimated by tritiated thymidine suicide rose from 45.2% to 68.4% (P less than 0.05) in the case of CFU-e and from 16.4% to 45.1% (P less than 0.05) for BFU-e following treatment with rHuEPO thus indicating in-vivo sensitivity of both the primitive as well as the mature erythroid progenitors to the hormone. The fall in BFU-e numbers in the bone marrow after several months of treatment may be due to a loss of cells from this progenitor pool by maturation that is uncompensated by replacement from the pluripotential stem cell compartment.

Adult↗
PubMed1987

Preexisting human anti-murine immunoglobulin reactivity due to polyclonal rheumatoid factors.

We report that sera from healthy controls, patients with ovarian or lung cancer, and patients with rheumatoid arthritis all contain IgM polyclonal rheumatoid factors which recognize antigenic determinants on murine and to a greater extent human immunoglobulin IgG. The major part of this reactivity is directed against conserved, shared antigenic determinants present on both human and murine IgG. Such antigenicity resides in the protein and not the carbohydrate moiety of IgG, since deglycosylation of the target murine monoclonal antibody did not result in any loss of antibody binding. Studies comparing the binding of polyclonal and monoclonal rheumatoid factors (from patients with rheumatoid arthritis and mixed essential cryoglobulinaemia, respectively) to murine and human IgG show that the antigenic determinants recognized by polyclonal rheumatoid factors are present on both whereas the antigenic determinant recognized by the monoclonal rheumatoid factors is present only on human IgG. Furthermore, patients with rheumatoid arthritis display an elevated human IgM anti-murine immunoglobulin response similar to that seen in cancer patients who have received murine monoclonal antibody therapy. We therefore conclude that, where possible, F(ab')2 fragments of murine monoclonal antibodies should be used for in vivo tumor localization studies to avoid possible immune complex formation, and that patients with rheumatoid arthritis should be considered to be possibly at higher risk of developing immune complex disease, were these rheumatoid factors to bind to the administered murine antibodies in vivo.

Animals↗
PubMed1987

Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis.

The diagnosis and management of Wegener's granulomatosis and microscopic polyarteritis are complicated by the lack of specific diagnostic tests. The diagnostic performance of a solid-phase radioimmunoassay, which detects the autoantibodies against neutrophil cytoplasm present in these disorders, was assessed in a prospective study of patients with suspected vasculitis and/or rapidly progressive nephritis. The assay had a sensitivity and specificity of 96% when carried out in combination with a specific inhibition stage and indirect immunofluorescence staining of alcohol-fixed normal neutrophils.

Autoantibodies↗
PubMed1987

Renal impairment following biliary tract surgery.

Postoperative mortality has been directly attributed to renal failure in approximately 5 per cent of patients after surgery for obstructive jaundice. An analysis of 334 patients undergoing biliary tract surgery was undertaken to identify the perioperative factors associated with the development of renal impairment, and to estimate the contribution of renal failure to mortality. Thirty-eight patients (11 per cent) developed postoperative renal impairment (a two-fold increase in serum creatinine postoperatively or a rise of greater than 100 mumol/l). Ninety-three factors were examined in these and 196 control patients. Stepwise logistic regression analysis identified only three factors which were significantly associated with renal impairment: postoperative sepsis (P less than 0.0005), pre-operative serum bilirubin (P less than 0.0005), and pre-operative urea (P less than 0.05). Renal impairment developed at a median 4 days after surgery and was associated with a median of two additional major postoperative complications, particularly sepsis and haemorrhage, for which 17 patients underwent reoperation. Twenty-eight (74 per cent) of the patients with renal impairment died in hospital, but in only one case was the cause of death directly related to renal failure. Twenty patients received specific therapy for renal failure, but only one of these survived. Pre-operative obstructive jaundice and postoperative infection are the major factors associated with renal impairment after biliary tract surgery. Renal impairment appears to be related to postoperative complications rather than directly to the surgical procedure itself. The development of postoperative renal impairment predicts a low chance of survival but appears to be an indicator, rather than a direct cause of a poor prognosis.

Acute Kidney Injury↗
PubMed1987

Monoclonal antibodies to restricted and cross-reactive idiotopes on monoclonal rheumatoid factors and their recognition of idiotope-positive cells.

Four human monoclonal rheumatoid factors (MRF) were used to raise a panel of mouse monoclonal antibodies (mAb) which were selected in a solid-phase radioimmunoassay for binding to MRF but not normal IgM. Three mAb, each raised against a different MRF, bound to the majority of MRF and also to most polyclonal RF. Four other mAb bound selectively to the MRF against which they were raised and to no other MRF, and rarely to any polyclonal RF. Competition studies using cold and radiolabeled mAb further indicated that these mAb recognize distinct and different epitopes on MRF. RF activity of MRF was inhibited by 3 of the 4 mAb binding to a single MRF and 2 of the 3 mAb binding to multiple RF. It was thus concluded that of this panel of mAb 3 recognized cross-reactive idiotopes and the remainder demonstrated highly restricted idiotopes on MRF. These mAb identified MRF idiotope-bearing cells in the peripheral blood of 3 of the MRF donors (and a further subject with type II essential cryoglobulinemia), with a frequency ranging from 0.3-10% of all mononuclear cells with the mAb to restricted idiotopes or 1.5-17% with mAb to cross-reactive idiotopes. These anti-idiotopic mAb should thus provide a highly specific means of identifying and monitoring MRF-producing cells in vivo.

Antibodies, Monoclonal↗