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B A Pussell

Publications and source records attributed to B A Pussell.

At least 37 records · Page 2Linked to original sources
PubMed1989

Hypercatabolism of C3 and C4 in active and inactive systemic lupus erythematosus.

The metabolism of the complement proteins C3 and C4 was studied in patients with active and inactive systemic lupus erythematosus (SLE) using highly purified, functionally active preparations. Nine patients with active and eight with inactive SLE were examined and 11 control subjects. There was a significant difference in the level of double stranded DNA antibodies, immune complexes, and serum C4 between the patients with active and inactive disease. Seven of 16 patients had detectable C4 null alleles and four had low serum concentrations of complement inhibitors. Each subject received approximately 370 kBq [125I]C4 and 93 kBq [131I]C3. Both patient groups showed significant C4 hypercatabolism compared with control subjects, but there was no difference between patients with active and inactive disease. The fractional catabolic rate (FCR) of C4 was comparable in subjects with and without detectable C4 null alleles. C4 production rate was significantly lower in patients with active SLE than in control subjects. There was significant C3 hypercatabolism for both patient groups, but C3 production was normal. An inverse correlation was observed between serum concentration and FCR. There was a highly significant correlation between C4 FCR and C3 FCR for control subjects + patients with inactive disease but not for those with active SLE combined with either controls or the inactive group. We conclude that complement hypercatabolism occurs in SLE irrespective of disease activity and that accelerated turnover does not account completely for the low C4 concentration observed in patients with active disease. This low concentration also results from impaired plasma production, which could reflect a high incidence of C4 null alleles or (inhibitory) factors associated with pathological complement activation, or both. Low C4 production could affect generation of the C3 converting enzyme C4b, 2b and thus influence proceeding complement activation.

Alleles↗
PubMed1989

Differences in the metabolism of C4 isotypes in patients with complement activation.

The metabolism of the C4 allotypes C4A3,B1 and C4A3,BO was studied in five healthy control subjects and six patients with active immunological disease (five with systemic lupus erythematosus and one with rheumatoid arthritis). The specific aim was to identify any differences in the metabolism of C4A and C4B gene products that may be linked to their documented functional differences in vitro. The fractional catabolic rate of C4A3,B1 in patients was significantly greater than that of C4A3,BO (3.98 +/- 1.37 versus 3.31 +/- 0.85%/h; mean +/- s.d.; P less than 0.05) but there was no difference in control subjects (1.95 versus 1.99%/h). The extravascular:intravascular (EV:IV) distribution ratio of C4A3,B1 was also greater in both patients (1.19 +/- 0.36 versus 0.97 +/- 0.35; P less than 0.01) and controls (0.43 +/- 0.11 versus 0.31 +/- 0.13; P = 0.01). We conclude that C4B1 was catabolized more rapidly than C4A3 in patients with pathological complement activation but not in control subjects. This difference could reflect the relatively greater extravascular distribution (i.e. EV:IV ratio) of C4B at sites of immune complex deposition or, alternatively, different rates of catabolism of inactive C4 isotypes (iC4b).

Alleles↗
PubMed1987

The complement system in type 1 (insulin-dependent) diabetes.

The complement proteins C1q, r, s, C2, C4, C3, factor B, C5, C6, and the inhibitors, C1 inhibitors, factors I and H were measured in 35 patients with recently diagnosed Type 1 (insulin-dependent) diabetes, 76 patients with longer-duration disease (30 with complications) and 43 first-degree healthy relatives. We found that C1q, C4 and C3 were reduced significantly in all groups of patients (p less than 0.001 for each protein in recent onset and uncomplicated patients; p less than 0.01, p less than 0.01 and p less than 0.05 respectively, for patients with complications) compared to 60 control subjects and that C4 was also reduced in healthy relatives (p less than 0.001). C4 allotypes were examined in 63 subjects (selected from the patient groups) in order to clarify the role of null alleles in the production of the C4 abnormality. These showed serum C4 to be reduced significantly in 50 patients without null alleles (patient mean 0.24 g/l; control subject mean 0.34 g/l) (p less than 0.0001), although levels were lowest in the 13 patients with one or more null alleles (mean 0.19 g/l). Finally, to examine the metabolic basis for the low concentrations of C4 and C3, the turnover of highly-purified, radiolabelled C4 and C3 was measured in seven recently diagnosed patients; four of these had low levels of C4. The data showed that three out of four of these patients had reduced synthesis of C3 and C4 and normal values for fractional catabolic rate. Two patients showed features of C4 hypercatabolism. We conclude that several early complement proteins are reduced in Type 1 diabetes, irrespective of duration or complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Detection of lymphocytotoxic antibodies in relatives of patients with type I diabetes.

Concentrations of lymphocytotoxic antibodies were measured in serum samples from 19 patients recently diagnosed as having type I diabetes and 43 healthy relatives (33 consanguineous and 10 non-consanguineous). The specificity of the reaction was tested at 15 degrees C and 37 degrees C against T lymphocytes and purified helper/inducer and cytotoxic/suppressor subsets. The concentrations of lymphocytotoxic antibodies in each of the three test groups were significantly higher than those in controls (type I patients, p less than 0.005; consanguineous relatives, p less than 0.001; and non-consanguineous relatives, p less than 0.002). The frequency of detection of the antibodies was also greater in each of the study groups (p less than 0.01, p less than 0.01, and p less than 0.05, respectively). Cytotoxicity affected both subsets at 15 degrees C but only cytotoxic/suppressor cells at 37 degrees C. The findings of lymphocytotoxic antibodies in healthy relatives of type I diabetics, irrespective of consanguinity, suggests that an environmental agent such as a virus is at least partially responsible for this lymphocytotoxic effect. Furthermore, the residual cytotoxic/suppressor cell killing at 37 degrees C could explain the defect of suppressor cells observed in these patients.

Adolescent↗
PubMed1985

Human fibronectin metabolism.

The metabolic behavior of fibronectin (Fn), a highly adhesive glycoprotein (440,000 mol wt), was studied in eight healthy control subjects and in 11 patients, six of whom were critically ill. Fn was purified from fresh human plasma, radiolabeled, and shown to retain function both in vitro and in vivo. Results showed that, in normal controls, Fn is a rapidly catabolized protein with a fractional catabolic rate (FCR) of 4.81%/h (range, 4.00-6.27), a half-life (t1/2) of 25 h (20-30), extravascular/intravascular diffusion ratio (EV/IV) of 2.04 (1.52-3.30), and a synthesis rate (SR) of 0.71 mg/kg body weight per h (0.61-0.87). There was evidence for extravascular catabolism in each subject. Plasma levels correlated with SR but not with t1/2 or FCR. Patients had a lower EV/IV ratio, and in two critically ill patients with low plasma Fn concentration the SR was markedly depressed. These findings suggest that reduced synthesis of Fn, rather than increased FCR or increased extravascular distribution, is responsible for Fn deficiency in critically ill patients.

Adult↗
PubMed1985

Verapamil prevents post-transplant oliguric renal failure.

Verapamil has proven effective in preventing acute renal failure in animal models if given prior to the insult and hence possibly has a role in the preservation of cadaveric renal tissue for transplantation. Twenty renal donors were randomly assigned to treatment (receiving verapamil 20 mg intravenously) and control groups. Recipients were monitored for renal failure by urine output and serum creatinines on days 1 and 7 and dialysis requirement to one week. Early urine outputs and serum creatinines (day 1) were significantly better in the treated than control group (p greater than 0.01, 0.05 respectively). We conclude therefore that verapamil may prevent post-transplant acute renal failure, but its optimal dosage and route of administration remain to be determined.

Acute Kidney Injury↗
PubMed1984

C3 metabolism in acute glomerulonephritis: implications for sites of complement activation.

Immunochemical and metabolic studies of complement were performed in 11 patients with acute poststreptococcal glomerulonephritis (AGN) to determine the mechanism(s) of hypocomplementemia. Four patients with profound reduction in serum C3 showed metabolic changes comparable to those seen in hypocomplementemic mesangiocapillary GN (MCGN), that is, nonlinear plasma disappearance of 125I.C3 and a gross (that is, 30-fold) reduction in C3 synthesis (0.01 to 0.02 mg/kg/hr); fractional catabolic rate (FCR) and extravascular/intravascular distribution (EV/IV) ratio were also increased (3.02 to 6.99%/hr; 1.14 to 2.96, respectively). The remaining seven patients had less (or no) reduction in C3 and showed normal or elevated values for all three metabolic parameters; six had linear plasma disappearance curves. Metabolic data in five simultaneously studied control subjects were FCR: 1.56 to 2.12%/hr; EV/IV ratio: 0.12 to 0.41 and synthesis rate: 0.30 to 0.52 mg/kg/hr. C3 nephritic factor (NeF) could not be detected in any sera and a significant reduction in serum C5 accompanied the changes in C3 (r = 0.89; P less than 0.001). Previous studies of C3 NeF-associated MCGN show that the fluid phase alternative pathway convertase seen in this condition has little or no C5 cleaving ability. We propose, therefore, that complement activation in AGN occurs via a surface-bound convertase which is capable of cleaving both C3 and C5. The glomerular capillary could provide such a site for activation.

Adolescent↗
PubMed1984

Factors influencing reticulophagocytic function in insulin-treated diabetes.

The splenic component of reticulophagocytic function (RPF) was examined in 29 insulin-treated diabetic subjects (13 type I and 16 type II) by measurement of clearance of altered, radiolabeled, autologous erythrocytes. Double-isotope studies were performed with cells altered by: (1) preincubation with N-ethylmaleimide (NEM) and (2) coating with IgG antibody to the Rhesus (Rh) D antigen, labeled with 99mTc and 51Cr, respectively. HLA typing for the A, B, and DR loci was performed in those patients showing a defect in the clearance of IgG-coated cells. Values for half-life (t1/2) were correlated with the incidence of diabetic complications, levels of HbA1, and circulating immune complexes (CIC). Two patterns of abnormal clearance were observed: first, an isolated defect of IgG-coated cell clearance in 7 patients (3 had the HLA B8/DR3 haplotype) and second, abnormal removal of both types of cell in a further 7 patients (3 had B8/DR3). There was no correlation between half-lives as measured by the two methods, although exclusion of the patients with a defect of IgG-coated cell clearance alone yielded a highly significant correlation for the remaining 15 Rh-positive patients (P less than 0.01). Abnormalities of IgG-coated cell clearance were more frequent in patients with HbA1 greater than 9% (P less than 0.02), while t1/2 of NEM-altered cells was significantly greater in patients with CIC (P less than 0.05). There was no correlation between t1/2 and the incidence of peripheral complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Does insulin administration contribute to immune complex formation in diabetes?

The effect of insulin administration on immune complex (IC) formation in diabetic patients was analysed in vivo and in vitro. Firstly, serial studies of IC status were performed over a mean period of 18 months in 44 diabetic patients, 37 of whom were receiving standard insulin therapy. Thirty patients changed to monocomponent (MC) insulin while seven commenced MC insulin after tablet failure. The other seven patients remained on standard insulin throughout the study. Secondly, nine patients had serial measurements of IC over a 6-8 h period following a routine morning dose of MC insulin; eight control subjects were similarly studied. The insulin content of IC in insulin treated patients was assessed in vitro by examining, (a) the selective precipitation of antibody bound insulin by 3% polyethylene glycol (PEG) and (b) the insulin specificity of antisera raised against PEG precipitates of IC positive sera. The longitudinal study of circulating IC showed no significant changes apart from an isolated fall in IgA containing IC at 6 months after changing therapy (P less than 0.05). No short term change in IC was observed after MC insulin administration. The precipitability of antibody bound insulin in insulin treated patients was not significantly different to that seen in non-insulin treated patients or normal sera. Antisera to PEG precipitates of diabetic sera showed no significant specificity for insulin, although they showed marked reactivity with other plasma components (such as immunoglobulins and complement components). It is concluded that administered insulin plays little or no role in IC formation in insulin treated diabetic patients.

Aged↗
PubMed1983

Mesangial IgA nephropathy: detection of defective reticulophagocytic function in vivo.

The splenic component of the reticulophagocytic system (RPS) was studied in 20 patients with primary mesangial IgA nephropathy and 15 healthy controls. Eight patients were hypertensive, seven had renal failure and six had significant proteinuria. RPS function was assessed by the measurement of T1/2 clearance of altered, radio-labelled autologous erythrocytes. Three different methods were used to alter the red cells - thermal stress, sulfhydryl inhibition with N-ethylmaleimide (NEM) and antibody-coating - and in 12 patients two of these methods were used simultaneously in double-isotope-labelled studies. Impaired clearance was demonstrated in 16 of the 20 patients. T1/2 of NEM-altered cells was abnormal in 12 of 19 studies in 17 patients (i.e. T1/2 greater than 22.5 mins) while T1/2 of IgG-coated cells was abnormal in 8 of 10 patients (i.e. T1/2 greater than 62 mins). The clearance of thermally-damaged cells was not significantly different from that observed in controls (normal range: 10.5-17 mins). In the double-isotope studies, the clearance of NEM-altered cells correlated with the clearance of IgG-coated cells (P less than 0.05). There was no correlation between T1/2 clearance times and circulating immune complexes. These abnormalities of splenic function suggest there is a primary reticulophagocytic defect in patients with mesangial IgA nephropathy. This finding could bear relevance to the pathogenesis of the disease.

Adolescent↗
PubMed1983

Wegener's granulomatosis: observations on 18 patients with severe renal disease.

Eighteen patients with Wegener's granulomatosis with renal involvement have been studied. Their course before treatment has indicated how the disease may progress and has provided a framework for diagnosis based on clinical and radiological features combined with available histology. The need for such diagnostic criteria is emphasised by the fact that a firm histopathological diagnosis could only be made in nine patients. A strong association between Wegener's granulomatosis and previous suppurative or tuberculous respiratory infection has been noted as well as between intercurrent infection and relapse. Evidence that immune complexes play a pathogenetic role has come from the association between active disease and circulating immune complexes. The observation of a reversible abnormality of splenic clearance of altered red cells suggests that immune complex handling by the spleen is defective. Treatment of these patients has shown a surprising degree of reversibility in many manifestations, especially renal failure. Remissions occurring spontaneously or induced by steroids alone are temporary and steroids, if used alone, may adversely affect outcome. While confirming the central role of cyclophosphamide in the induction of remission, this study has indicated that its combination with steroids and/or plasma exchange may be valuable in initial control of fulminating disease. The fact that seven patients died during induction (as well as a further four in the succeeding five years) reflects the advanced disease at presentation and the infective problems associated with immunosuppressive therapy. This highlights the need for earlier diagnosis.

Adrenal Cortex Hormones↗
PubMed1983

Normal human serum inhibits the lymphocytotoxicity of sera from patients with infectious mononucleosis.

The inhibitory effects of normal human serum (NHS) on the lymphocytotoxic activity (LCA) of sera from patients with infectious mononucleosis (IM) were investigated. Dilution of IM serum with complement fixation diluent (CFD) caused a significant rise in LCA at 1/10 dilution (P less than 0.001) followed by a steady decline at higher dilutions. In contrast, 1/10 dilution with pooled NHS caused a gross reduction in lymphocyte killing (P less than 0.01). This reduction occurred irrespective of the order of incubation of NHS and IM serum with target lymphocytes. Pre-dilution of the NHS showed this inhibitory effect to be dose-responsive. Further characterization of the inhibitor(s) showed it to reside in the exclusion peak of Sephadex G-200, to be abolished by treatment with the sulphydryl inhibitors, 2-mercaptoethanol and iodoacetamide and to be depleted selectively by incubation with monospecific anti-IgM (but not anti-C1q or anti-alpha 2-macroglobulin). The site of the inhibitory reaction was examined by indirect immunoperoxidase staining of the lymphocyte surface with monospecific anti-IgM and peroxidase conjugated swine anti-rabbit immunoglobulin. This showed that pre-incubation of IM serum with NHS caused a significant reduction in IgM positive cells compared to that observed with IM serum diluted in CFD alone. It is concluded that certain IgM molecules, present in NHS, inhibit the complement-mediated LCA of IM sera. This inhibition occurs by fluid phase interference with surface deposition of cytotoxic IgM rather than by competitive surface binding. The presence of such serum-serum interactions emphasises the complexity of the lymphocytotoxin reaction and the need for caution in attributing abnormalities in vivo to cytotoxic phenomena measured in vitro.

Antilymphocyte Serum↗
PubMed1982

Complement behavior in infectious mononucleosis: possible mechanisms for the prevention of immune complex injury.

The acute-phase complement reaction was examined in patients with uncomplicated infectious mononucleosis (IM). Concentrations of both complement and complement inhibitor protein were significantly elevated during the acute phase, and turnover studies with purified 125I-labeled C3 showed this increase to result from increased C3 synthesis. Nine of 16 patients had evidence of in vivo complement activation during this period. Despite high levels of C1q-binding immune complexes in most acute-phase sera from patients with IM, the capacity of these sera to solubilize immune precipitates in vitro was normal. In contrast, four of five sera from patients with active systemic lupus erythematosus showed reduced solubilization. The level of C3b inactivator in sera from patients with IM and the percentage conversion of C3 after in vitro complement activation by aggregated IgG were inversely correlated (P less than 0.01). It is proposed that an acute-phase complement reaction limits immune complex-mediated injury to tissue by maintaining those complement functions that are required for the effective processing of circulating antigen/antibody material.

Adolescent↗