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Biomedical subjects

D G Williams

Publications and source records attributed to D G Williams.

At least 127 records · Page 7Linked to original sources
PubMed1984

Lack of effect of tryptophan treatment in demented gerontopsychiatric patients. A double-blind, crossover-controlled study.

Twenty-eight elderly patients with dementia and in many cases also depression received daily treatment with either L-tryptophan (3g in the evening) or casein (control substance) for 1 month each, using a crossover design and double-blind procedures. Each patient's mental condition and performance ability were rated, and biological variables (serum tryptophan levels, platelet 5-HT uptake, platelet MAO activity, red blood cell thiamine, pyridoxine and riboflavin levels) were measured. Serum tryptophan levels were elevated by tryptophan treatment, but the treatment failed to have significant effects on the mental condition of the patients as a whole. Dividing the patients into two groups on the basis of the treatment during which they received their best behavioral rating failed to show significant relations to biological variables, except for differences between Vmax values for platelet 5-HT uptake. The findings indicate that long-term administration of tryptophan to gerontopsychiatric patients does not generally have beneficial effects.

Aged↗
PubMed1984

Severe systemic vascular necrosis in cyclosporin-treated rabbits with acute serum sickness.

Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed a severe, systemic vascular injury, which was not similar to that normally seen in ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg), on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg/day from day -2 to +8, or 25 mg/kg/day from day -2 to +3 or day 0 to 5. Muscular arteries of the heart and splanchnic organs developed an arterial injury in which there was extensive fibrinoid necrosis of the vessel wall but little or none of the mononuclear cell reaction that is normally associated with the arteritis of ASS. A microvascular injury also occurred which led to interstitial haemorrhage in the gastric mucosa and multi-focal necrosis in the heart and liver. These lesions were seen with equal frequency in all groups of rabbits with serum sickness who received CyA, irrespective of whether they also received endotoxin. We suggest that CyA altered the host inflammatory response to the injury initiated by the BSA-anti-BSA immune complexes and this led to enhanced vascular injury. The inhibition by CyA of the perivascular cellular reaction suggests that this reaction may be mediated by T lymphocytes. This model should provide further insight into the pathogenesis of arteritis, as well as the mechanisms of cyclosporin toxicity.

Animals↗
PubMed1984

Human renal allograft and peripheral blood T lymphocyte subpopulations during the onset and treatment of rejection.

In order to study the changes in T lymphocyte subpopulations in both allografts and peripheral blood of patients following renal transplantation, we have examined 72 fine needle allograft aspirates and 56 peripheral blood samples from 24 patients during the first month following transplantation. The patients were studied before, during and after rejection episodes. Monoclonal antibodies directed against T helper (TH) and T cytotoxic/suppressor (TCS) cells were used to identify lymphocyte subpopulations in the allograft aspirates and peripheral blood. The ratio of TH:TCS cells in both the allograft aspirates and peripheral blood decreased significantly (p less than 0.01) during the three days before rejection became clinically manifest. During rejection, the aspirate TH:TCS ratios, but not the peripheral blood TH:TCS ratios, remained depressed. Following successful treatment for rejection, the aspirate TH:TCS ratios returned to levels found in non-rejecting allografts. However, in the allografts which were lost as a result of rejection or had persistent rejection despite treatment, the aspirate TH:TCS ratios, but not peripheral blood TH:TCS ratios, remained significantly low (p less than 0.01) when compared with the successfully treated allografts. Our study indicates that TH:TCS ratios, particularly in allograft aspirates, may be of value in predicting the onset and outcome of renal allograft rejection.

Adolescent↗
PubMed1984

Impaired lymphocyte and suppressor cell function in minimal change nephropathy, membranous nephropathy and focal glomerulosclerosis.

The response of lymphocytes to Concanavalin A (Con A) was measured in patients with the nephrotic syndrome due to minimal change nephropathy (11 patients), focal glomerulosclerosis (15 patients) and membranous nephropathy (21 patients); autologous serum was not used in these studies. There was a significant reduction in lymphocyte transformation in each group of patients compared to normal controls (p less than 0.01 for each group), but there was no significant difference between the individual groups of patients. Impaired lymphocyte transformation to Con A appears therefore to be a general feature of the nephrotic syndrome and is not exclusive to minimal change nephropathy. Measurements of suppressor cell function in 4 patients with minimal change nephropathy, 9 patients with focal glomerulosclerosis and 12 patients with membranous nephropathy were performed at the same time as the above studies. In each group suppressor cell function was decreased, indicating that the impaired lymphocyte response to Con A is not due to increased suppressor cell activity. These findings do not support the hypothesis that an abnormality of lymphocyte function peculiar to minimal change nephropathy is pathogenetic in that disease and not in other causes of the nephrotic syndrome; it seems more likely that the abnormalities described are secondary to the nephrotic state.

Adolescent↗
PubMed1984

Persistent anti-DNA antibodies and DNA-anti-DNA complexes in post-streptococcal glomerulonephritis.

Two patients with the typical clinical, serological and pathological features of acute post-streptococcal glomerulonephritis were found to have elevated serum concentrations of DNA-anti-DNA complexes, and, in one case, of anti-DNA antibody, both single and double stranded. The DNA-anti-DNA complexes were found to persist for 15 and 21 months respectively following the initial illness, despite rapid resolution of the clinical features and severe renal dysfunction. It is suggested that the DNA-anti-DNA complexes may have a pathogenetic role in post-streptococcal nephritis, or alternatively act as a marker of those patients who will develop nephritis after a streptococcal infection.

Acute Disease↗
PubMed1984

End-stage renal failure in systemic lupus erythematosus with nephritis.

The survival of patients in end-stage renal failure from lupus nephritis offered renal substitution therapy has been the subject of conflicting reports. Trying to clarify the reasons for this discrepancy, we analysed our experience with dialysis and transplantation in systemic lupus erythematosus (SLE). Of our 138 patients with lupus nephritis, 26 reached end-stage renal failure, of whom 24 received replacement therapy. Fourteen patients had a marked acute deterioration in renal function immediately before reaching terminal uremia, associated with active SLE in 12 and acute tubular necrosis after hypotension in one. Nine patients in this group died, 8 within 1 month of beginning dialysis. Nine patients progressed slowly to endstage renal failure over 2 to 7 years, without evidence of active SLE: only 1 required aggressive treatment and only 3 patients died, 1 five years after transplantation. Eight patients received altogether 10 allografted kidneys; 4 still functioning 10-24 months later; 2 patients are back on dialysis and 2 died, 1 of a myocardial infarct. There was no evidence of active SLE after transplantation. Ten patients were dialysed for more than 3 months; most were maintained on prednisolone and azathioprine whilst on dialysis and lupus activity tended to abate. The exclusion of the group of patients with rapid pre-terminal decrease in renal function from some series may explain some of the differences in reported survival. Stable patients with SLE present few problems in end-stage renal failure or after transplantation.

Adult↗
PubMed1984

Vasculitis affecting the kidney: presentation, histopathology and long-term outcome.

Fifty-three patients who by clinical and/or histological criteria were judged to have vasculitis affecting the kidney were reviewed. Patients with systemic lupus or Schönlein-Henoch purpura were excluded. Segmental necrotising glomerulitis was taken as a manifestation of vasculitis ('microscopic polyarteritis'). Those patients in whom vasculitis was confined to glomerular capillaries were compared with those who in addition had vascular lesions outside the glomeruli. The two groups were found to have identical clinical features. Clinical presentation was predominantly extrarenal, and exclusively renal in only two. Three patients were classified histologically as Wegener's granulomatosis, four had malignant tumours and two relapsing polychondritis. Hepatitis B surface antigen was absent in all of 37 patients tested. Renal disease presented with microscopic haematuria and minor proteinuria in the majority (32) but 16 patients presented with rapid deterioration of renal function, including seven with anuria. Histologically 42 patients showed segmental necrotising glomerulitis ('microscopic polyarteritis'), six diffuse proliferative glomerulonephritis,and in five only minor or ischaemic glomerular changes were present. Crescents were found in 41/42 of those with segmental necrotising glomerulitis, nd involved more than 50 per cent of glomeruli in 15 patients. Immunohistochemical studies were generally negative except the fibrin. Electron microscopy showed no evidence of immune deposits in necrotising glomerulitis, but these were present in 2/6 patients with diffuse proliferative glomerulonephritis. Overall prognosis was poor, 35 patients having died, 20 early in the course of the disease and 15 later. Oligoanuria and extensive crescent formation were adverse signs. Survivals were 54, 38 and 34 per cent at one, five and 10 years respectively. Of those who survived the initial illness, 12 were stable with apparently inactive disease, whilst 16 continued to show clinical signs of activity and required treatment. A variety of treatments was employed including oral and intravenous corticosteroids, immunosuppressive agents, anticoagulants; only one patient was treated by plasmapheresis. It is difficult to draw any firm conclusions as to the efficacy of treatment and survival rates remain unsatisfactory.

Acute Disease↗
PubMed1984

Glomerular thrombosis and cortical infarction in cyclosporin-treated rabbits with acute serum sickness.

Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed glomerular capillary thrombosis and cortical infarction, lesions not seen in unmodified ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg) on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg from day -2 to +8, or 25 mg/kg/day from day -20 to +3 or day 0 to 5. Signs of this renal injury were haematuria, transient proteinuria, glycosuria and oliguria and they occurred during the rapid phase of antigen elimination when immune complexes were being formed. Seventeen of the 33 rabbits developed glomerular capillary thrombi and 11 of 17 also had glomerular and tubular infarction. Electron microscopic examination showed that these lesions were associated with severe endothelial injury and platelet-fibrin-leucocyte thrombi. These changes were more severe in the groups given 25 mg/kg. The lesions were not seen in untreated rabbits and ASS, nor in normal rabbits given equivalent doses of CyA alone. A strikingly similar renal lesion has been seen in patients receiving CyA following bone marrow transplantation, and also in the haemolytic uraemic syndrome. The model we describe may be valuable for the study of the mechanisms of endothelial injury and thrombosis in the kidney.

Animals↗
PubMed1984

Complement activating cryoglobulins in the nephritis of systemic lupus erythematosus.

Complement activation in vitro by cryoglobulins isolated from the sera of 28 patients with systemic lupus erythematosus (SLE) was examined by incubating the cryoglobulin with normal human serum and performing crossed-immunoelectrophoresis of the mixture to detect C3 conversion. Eighteen of the 28 SLE cryoglobulins activated complement; eight by the classical pathway, four by the alternative pathway exclusively, and six by both pathways. In contrast only two out of 20 cryoglobulins isolated from the sera of normal subjects activated complement and both did so by the classical pathway. Twenty-three of the 28 SLE sera activated complement and complement activating cryoglobulins were isolated from 15 of these 23 sera. The parent sera of cryoglobulins activating complement had lower C4 and C3 concentrations than sera whose cryoglobulins did not split complement but these differences were not significant. The ability of SLE cryoglobulins to activate complement in vitro suggests that these immune complexes activate complement in vivo and thus may contribute to tissue damage in this disease. The activation of both classical and alternative complement pathways is in keeping with other evidence that both pathways are involved in SLE.

Adult↗
PubMed1983

Effect of Cyclosporin A on prostacyclin synthesis by vascular tissue.

NZW rabbits with acute serum sickness given Cyclosporin A (CyA) 25 mg/kg/day develop glomerular capillary thrombosis similar to that seem in the haemolytic uraemic syndrome (HUS). Bone marrow recipients treated with CyA may also develop a similar renal lesion associated with a haemolytic uraemic-like syndrome. In the HUS, impaired production of prostacyclin by vascular tissue may be found and has been associated with a lack of a plasma factor which stimulates prostacyclin synthesis. We therefore examined, in six normal rabbits, treated with CyA 25 mg/kg for five days, the ability of plasma from treated and untreated rabbits to stimulate prostacyclin synthesis from normal rabbit aortic rings. Plasma from untreated rabbits produced 21.5 +/- 6.9 ng 6-keto PGF1 alpha/ml/mg wet weight aorta (mean +/- SEM). However, the ability of plasma from CyA-treated rabbits to stimulate prostacyclin production was profoundly reduced. This was apparent within 24 hours of starting and persisted for seven days after therapy was stopped: mean of values from all rabbits bled from start of therapy until seven days after therapy stopped was 3.7 +/- 0.5 ng/ml/mg. We suggest that the renal complications of CyA therapy are related to a failure of normal vascular prostacyclin synthesis due to lack of a prostacyclin-stimulating plasma factor.

Animals↗
PubMed1983

The identification and characterization of two separate carboxylesterases in guinea-pig serum.

The esterase activity of guinea-pig serum was investigated. A 3-fold purification was achieved by removing the serum albumin by Blue Sepharose CL-6B affinity chromatography. The partially purified enzyme preparation had carboxylesterase and cholinesterase activities of 1.0 and 0.22 mumol of substrate/min per mg of protein respectively. The esterases were labelled with [3H]di-isopropyl phosphorofluoridate (DiPF) and separated electrophoretically on sodium dodecyl sulphate/polyacrylamide gels. Two main labelled bands were detected: band I had Mr 80 000 and bound 18-19 pmol of [3H]DiPF/mg of protein, and band II had Mr 58 000 and bound 7 pmol of [3H]DiPF/mg of protein. Bis-p-nitrophenyl phosphate (a selective inhibitor of carboxylesterase) inhibited most of the labelling of bands I and II. The residual labelling (8%) of band I but not band II (4%) was removed by preincubation of partially purified enzyme preparation with neostigmine (a selective inhibitor of cholinesterase). Paraoxon totally prevented the [3H]DiPF labelling of the partially purified enzyme preparation. Isoelectrofocusing of [3H]DiPF-labelled and uninhibited partially purified enzyme preparation revealed that there were at least two separate carboxylesterases, which had pI3.9 and pI6.2, a cholinesterase enzyme (pI4.3) and an unidentified protein that reacts with [3H]DiPF and has a pI5.0. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of these enzymes showed that the carboxylesterase enzymes at pI3.9 and pI6.2 corresponded to the 80 000-Mr subunit (band I) and 58 000-Mr subunit (band II). The cholinesterase enzyme was also composed of 80 000-Mr subunits (i.e. the residual labelling in band I after bis-p-nitrophenyl phosphate treatment). The unidentified protein at pI5.0 corresponded to the residual labelling in band II (Mr 58 000), which was insensitive to neostigmine and bis-p-nitrophenyl phosphate. These studies show that the carboxylesterase activity of guinea-pig serum is the result of at least two separate and distinct enzymes.

Animals↗
PubMed1983

Successful treatment of middle aged and elderly patients with end stage renal disease.

Many patients over the age of 55 with end stage renal disease in the United Kingdom are denied dialysis or transplantation. Although the reasons are complex, anticipation of a poor prognosis for these patients might explain why most British renal units impose an arbitrary age limit on the acceptance of patients for treatment. A study was therefore conducted to examine the prognosis and quality of life of 84 patients (mean age 59.6 years, range 55-72) accepted into our renal replacement programme from the beginning of 1975. The five year survival of the patients was 62.0% with 78.1% of the survivors either having successful transplants or caring for themselves using home haemodialysis or continuous ambulatory peritoneal dialysis. The results show that in terms of survival, economics, and rehabilitation it is both feasible and reasonable to treat middle aged and elderly patients with end stage renal disease. These patients should therefore not be denied dialysis or transplantation on the basis of age alone, and the lack of resources and other factors that allow this state to persist in Britain should be rapidly redressed.

Age Factors↗
PubMed1983

High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.

Adolescent↗
PubMed1983

Intramolecular group transfer is a characteristic of neurotoxic esterase and is independent of the tissue source of the enzyme. A comparison of the aging behaviour of di-isopropyl phosphorofluoridate-labelled proteins in brain, spinal cord, liver, kidney and spleen from hen and in human placenta.

Neurotoxic esterase activity was measured in homogenates of human placenta and hen brain, spinal cord, liver, kidney and spleen. The activity in liver comprised less than 20% of the Paraoxon-resistant esterases, but in the other tissues neurotoxic esterase accounted for over 50%. The same tissues were labelled with [3H]di-isopropyl phosphorofluoridate, and any isopropyl group transferred on to protein during 'aging' of the labelled enzymes (alkali-volatilizable tritium) was measured. No Paraoxon-sensitive labelled sites were found to age in this way in any tissue. In brain, the Paraoxon-resistant alkali-volatilizable-tritium-labelled sites correlated with the number of neurotoxic esterase labelled sites, indicating that 'aging' and isopropyl group transfer were 100% efficient. The site receiving the transferred isopropyl group was characterized by analysing the distribution of radiolabelled proteins on gel-filtration chromatography in the presence of SDS. In particulate preparations from each tissue, the protein-bound alkali-volatilizable tritium (transferred isopropyl group) was attached to a polypeptide of Mr 178 000. This same polypeptide also bore the isopropyl-phosphoryl group of neurotoxic esterase, indicating that aging of neurotoxic esterase is an intramolecular group transfer. The apparent turnover number for the enzyme (average 1.6 X 10(5) min-1) was approximately the same in each hen tissue, confirming that closely similar enzymes were present in brain, spinal cord, liver and spleen. The apparent turnover for the human enzyme was 1.8-fold higher than that for the hen enzyme. The concentration of the neurotoxic esterase phosphorylated subunit in brain, spinal cord, spleen, placenta and liver was 14.6, 3.8, 7.4, 3.3 and 3.8 pmol/g of tissue. The evidence indicated that neurotoxic esterase is present in each tissue except kidney, and that isopropyl group transfer on 'aging' occurs on this enzyme only. This process is an intramolecular transfer of the group within the same polypeptide.

Animals↗
PubMed1983

Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.

Of 104 patients with idiopathic mesangiocapillary glomerulonephritis studied for at least two years, 69 patients had type I disease and 35 had type II. Forty-five patients were children, and 59 were adults. Type II mesangiocapillary glomerulonephritis was more common in children than in adults, but no other clinical feature distinguished the two types at onset. Complement studies revealed that patients with type II had lower serum C3 concentrations and more frequently showed C3-splitting activity (C3 nephritic factor) in the serum. Children had hypertension or a lowered glomerular filtration rate less frequently at onset than did adults, but children had a higher incidence of a hematuric onset; C3 nephritic factor was also more frequent in the children. During a follow-up period of two to 21 years (mean eight years), only seven patients (five with type I and two with type II) showed clinical remission, whereas 38 percent of patients with type I and 49 percent of patients with type II died or required dialysis; a further 23 percent of patients with type I and 16 percent of patients with type II had continuing disease and reduced glomerular filtration rate. Only the presence and persistence of a nephrotic syndrome in type I predicted renal failure. In both types, the presence of sclerosis or crescents in the initial renal biopsy specimen was associated with a poorer prognosis, but no other feature was of major prognostic value.

Adolescent↗
PubMed1983

Cyclosporin A inhibits acute serum sickness nephritis in rabbits.

The effect of the immunosuppressive agent cyclosporin A (Cy A) on the renal injury in acute serum sickness was examined in rabbits. Serum sickness was induced in 23 untreated NZW rabbits by a single intravenous injection of bovine serum albumin (BSA) 250 mg/kg with E. coli endotoxin (5 micrograms/kg): BSA was eliminated after 8.6 +/- 0.16 days (mean +/- s.e. (mean]; proteinuria occurred in 19 (84%) and glomerular proliferation in 20 (87%) rabbits. When Cy A (15 or 25 mg/kg) was given daily by intramuscular injection, starting either 2 days before or at the time of induction of acute serum sickness, proteinuria was profoundly reduced and glomerular proliferation was inhibited. Even when rabbits were first treated with Cy A (25 mg/kg) 5 days after the induction of disease proteinuria and glomerular proliferation were similarly inhibited. When the treated animals were compared with controls there were no differences in the following: time to elimination of BSA, amount or size of circulating immune complexes, fall in serum C3 at immune elimination, or deposition of immune reactants in the glomeruli. These results show that Cy A inhibits the renal injury of acute serum sickness and indicate that T cells may play a role in mediating the nephritis in this condition.

Acute Disease↗