Biomedical subjects
Publications and source records attributed to D G Williams.
We present a sensitive colorimetric determination of 5'-nucleotidase based on the measurement of liberated phosphate by reaction with stannous chloride/molybdenum blue. No protein precipitation is required. The method is simple, sensitive, economical, and easy to use, and involves relatively stable reagents.
In order to determine whether circulating antigen-antibody complexes in systemic lupus erythematosus (SLE) consist of DNA and anti-DNA, cryoglobulins were isolated from the sera of 38 patients with SLE nephritis and analysed for DNA and anti-DNA. Cryoglobulins were detected in 36 of the 38 sera, and DNA was found in 30 of 33 examined by either fluorescence of ethidium bromide or a radioimmunoassay. Anti-DNA activity was not detectable in any of the whole cryoglobulins but anti-IgG activity was found in 17. Twenty cryoglobulins were therefore treated by acid dissociation and ultracentrifugation to obtain isolated immunoglobulins; IgG was isolated from all, and IgM from eight. Using a modified Farr assay to detect anti-dsDNA and an enzyme-linked immunoadsorption assay to detect anti-ssDNA, anti-dsDNA activity alone was found in five IgG fractions, anti-ssDNA activity alone in five, and both anti-ds- and anti-ssDNA activity in four. Anti-dsDNA activity was found in three of the IgM fractions. In all, anti-dsDNA activity was found in nine of these 20 cryoglobulins, and anti-DNA in 14. Analysis of these 14 cryoglobulins with anti-DNA Ig fractions showed that there was enrichment of the IgG anti-DNA activity in the cryoglobulin compared to the patient's serum in all but two cases. In six of the 20 cryoglobulins studied there was no detectable anti-DNA activity in isolated IgG or IgM fractions. We therefore concluded that DNA-anti-DNA complexes were present in most of our patients with SLE nephritis, but there was clearly a substantial minority in whom they were undetectable. In some of the latter who also had active disease the cryoglobulins had anti-IgG activity. Thus it would seem that SLE can occur in the absence of DNA-anti-DNA complexes, but with other complexes present. DNA was also found in cryoglobulins isolated from patients with idiopathic glomerulonephritis, but, in contrast to recent reports, anti-DNA activity was not detectable in immunoglobulins isolated from their cryoglobulins.
The case histories of nineteen patients who were seen in one renal unit between 1966 and 1978 and who were found to have primary amyloidosis are reviewed. Most were aged more than fifty and presented with the nephrotic syndrome without particular diagnostic features although electrophoresis of plasma and urine revealed abnormal immunoglobulins in a minority. Treatment was generally only symptomatic and most patients died within six months of diagnosis usually from renal failure. At the time of writing only the two patients treated by maintenance haemodialysis are still alive.
Sera from patients with the nephrotic syndrome due to minimal change nephropathy (11 patients), membranous nephropathy (14 patients) and focal glomerulosclerosis (15 patients) inhibited the response of normal lymphocytes to the mitogen Concanavalin A. Although there was a tendency for the sera of patients with minimal change nephropathy to be more inhibitory than sera from the other two forms of nephrotic syndrome, this effect of nephrotic sera on normal lymphocytes is not confined to minimal change nephropathy. Until the exact nature of the inhibitor(s) is established, it is therefore not possible to state that impaired lymphocyte transformation by serum plays a pathogenetic role specifically in minimal change nephropathy. The susceptibility of nephrotic patients to infection may be due in part to the sera of the patients causing reduced lymphocyte function in vivo which leads to a defective immune response.
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Changes in performance resulting from smoking were assessed in 48 male cigarette smokers who were classified both by daily consumption and by relative desire for smoking in situations inducive of high or low arousal. Each took part in four first cigarette of the day conditions involving a sham smoking control and three cigarettes differing in nicotine delivery. With increasing cigarette strength gains in letter cancellation speed on smoking increased although an inverted-U relationship was suggested; immediate memory accuracy progressively deteriorated once pre-smoking performance was controlled for. Smokers with greater desire to smoke in situations inducive of low arousal appeared to react more strongly to cigarettes and showed superior gain in cancellation speed on smoking. High cigarette consumption did not lead to between-day tolerance to cigarette effects.
75 children aged under 15 years have entered the regular haemodialysis/renal transplant programme at Guy's Hospital in the 10 years since its inception; 13 children have subsequently died. A combination of hospital and home haemodialysis and renal transplantation was used. 64 children received 80 renal allografts; 37 1st grafts were from live, related donors and 27 were from cadaver donors. The 5-year acturial patient survival for the whole group and for those who had transplants was 76%. Live donor graft survival was 65% at 3 years, and 55% at 5 years; 1st cadaver graft survival was 42% at 3 years. Results obtained during the last 6 years of the 10-year period showed an improvement with a live related donor graft survival rate of 71%, and a 1st cadaver graft survival rate of 47% at 3 years. Particular experience was gained with home haemodialysis and live, related donor transplantation. Despite growth, and psychosocial and rehabilitation problems, the overall results were encouraging, particularly for the 46 children who had successful transplants. These children grew better, had fewer psychosocial difficulties, and were rehabilitated more successfully into normal life than those on long-term dialysis. We conclude that dialysis and transplantation should be offered to all suitable children with terminal renal failure.
Although DNA and anti-DNA antibodies have been eluted from diseased tissues in systemic lupus erythematosus (SLE) it is uncertain whether DNA and anti-DNA comprise circulating antigen-antibody complexes in SLE. Cryoglobulins from 20 patients with SLE were examined for (i) DNA, using a radioimmunoassay and an ethidium bromide assay, (ii) anti-DNA activity of IgG and IgM, isolated from the cryoglobulins by ultracentrifugation at pH 3.5, by a modified Farr assay (anti-dsDNA) and a solid phase ELISA (anti-ssDNA). DNA was found in each of the 20 cryoglobulins by both methods. Isolated IgG had anti-DNA activity in 14 cryoglobulins: 5 anti-dsDNA, 5 anti-ssDNA and 4 anti-ds- and ssDNA; isolated IgM had anti-dsDNA activity in 3 cryoglobulins. Isolated IgG/IgM had no anti-DNA activity in 6 of the 20 cryoglobulins. In controls with idiopathic nephritis (11 membranous, 13 mesangio-capillary) DNA was detected in cryoglobulins, but no ati-DNA activity was found. It is concluded that circulating dsDNA-anti-dsDNA complexes are present in SLE, but some patients have SLE without these complexes. Our failure to find dsDNA-anti-dsDNA complexes in nephritis not due to SLE indicates the specificity of such complexes for SLE.
We have studied the fragmentation by pepsin in 1 M-acetic acid of the erythrocyte anion-transport protein in erythrocyte membranes. The location of the fragments obtained was determined by radioiodinating the protein with the use of lactoperoxidase, and identifying the labelled peptides obtained in peptide "maps" of thermolysin digests of the fragments. Three of the fragments were found to be related overlapping products, and shared a common C-terminus. The major site of pepsin cleavage leading to the C-termini of these fragments was shown to be close to the major site of extracellular cleavage of the protein by proteinases active at a neutral pH. Another two fragments were isolated and shown to be derived from the C-terminal portion of the protein. No well-defined large radioactive fragments of the protein were solubilized from the membrane by pepsin in 1 M-acetic acid, the bulk of the radioactivity attributable to the anion transport protein being recovered in very small fragments that could not be resolved by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. Our results suggest that the polypeptide chain of the anion-transport protein emerges at the extracellular face of the membrane 8000-13000 daltons on the N-terminal side of the major site of extracellular cleavage of the protein by proteinases that are active at a neutral pH.
On each of 4 days after abstaining from cigarettes and other psychoactive materials for at least 10 h, 48 male cigarette smokers reported their mood before smoking the first cigarette of the day. Smokers were classified both by relative desire for smoking in situations inducive of high arousal or low arousal and by average daily consumption. Greater relative desire for smoking in high-arousal situations was associated with an abstinence syndrome of dysphoria. Compared to smokers with low consumption, medium-heavy smokers showed higher levels of tension-anxiety and were less deactivated while at the same time they were more fatigued and sleepy, indicating different relationships with different components of multifactorial arousal. Effects related to levels of cigarette consumption may have been confounded by tea/coffee withdrawal, however, abstinence states disappeared on smoking.
The topology of the human erythrocyte membrane anion-transport protein (band 3) has been investigated by isolation and peptide 'mapping' of the major and minor fragments derived from proteolytic cleavage of the lactoperoxidase 125I-labelled protein in erythrocytes and erythrocyte membranes. The content, in each fragment, of lactoperoxidase 125I-labelled sites (which have a known location in the extracellular or cytoplasmic domain of the protein), together with the location of the sites of proteolytic cleavage yielding the fragments, has allowed us to determine the alignment of the fragments on the linear amino acid sequence and to infer the topology of the polypeptide in the membrane. The results suggest that a region in the C-terminal portion of the polypeptide forms part of the cytoplasmic domain of the protein in addition to a large N-terminal segment. The membrane-bound regions of the protein are located in the C-terminal two-thirds of the molecule. In this region the polypeptide chain traverses the membrane at least four times and an additional loop of polypeptide is either embedded in the membrane or also penetrates through it to the other surface. The location of the lectin receptors on the protein and the site of binding of an anion-transport inhibitor have also been studied.
The Olympus "Quickrate", a photometer built for both kinetic and end point analysis was evaluated in this laboratory. Aspartate transaminase, lactate dehydrogenase, hydroxybutyrate dehydrogenase, creatine kinase, alkaline phosphatase and gamma glutamyl transpeptidase were measured in the kinetic mode and glucose, urea, total protein, albumin, bilirubin, calcium and iron in the end point mode. Overall, good correlation was observed with routine methodologies and the precision of the methods was acceptable. An electrical evaluation was also performed. In our hands, the instrument proved to be simple to use and gave no trouble. It should prove useful for paediatric and emergency work, and as a back up for other analysers.
An improved interactive system for searching substructure and biological activity data has been developed. Features of the system include a two-level substructure search (fragment screen and atom by atom) and an expanded biological activity data base. The system operates on a file of about 150 000 compounds.
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One hundred and fifty four patients admitted to a general hospital psychiatric unit with a history of poor diet were examined. Serum pyruvate was estimated in all, red cell transketolase in 74 and red cell aspartate transaminase in 66. Significantly more of the 58 abnormally low thiamine patients than of the normal thiamine group showed clinical signs of malnutrition or were diagnosed as chronic alcoholics, drug addicts, schizophrenics or endogenous depressives. Significantly more endogenous depressives than other patients had a raised aspartate transaminase activity coefficient (pyridoxine lack.) While most low thiamine findings are probably manifestations of malnutrition pyridoxine lack may have some aetiological significance in endogenous depression.
The presence of cryoglobulins was investigated in ninety patients with recurrent oral ulcers (ROU) and sixty-one patients with Behçet's syndrome (BS). The immunodiffusion method was compared with Laser nephelometry for the analysis of IgG, IgM, IgA and C3 in cryoglobulins. Although the two methods of assessment showed a very significant agreement. Laser nephelometry was more sensitive than the double diffusion precipitation method and was used for quantitative analysis of cryoglobulins. The prevalence of any type of cryoglobulins was 64% in ROU and 75% in BS, as compared with controls (15%). In ROU significant levels of IgA were found in minor (P = 0.0196) and major (P = 0.0114) aphthous ulcers and to a lesser extent in herpetiform ulcers (P = 0.0624). Among the four types of BS signficant increases in C3 were found in the arthritic type (P = 0.0068) and ocular type (P = 0.0275), whereas IgM (P = 0.0031) and IgG (P = 0.0369) were increased only in the muco-cutaneous type. Sequential studies showed that disease remissions or exacerbations were correlated with a decrease or increase in IgM or IgG classes of cryoglobulins. However, the converse was found with IgA which may inhibit some functions of polymorphonuclear leucocytes, and this may be responsible for the failure to remove damaging IgG, IgM and C3 complexes from the circulation.