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Biomedical subjects

J Wadsworth

Publications and source records attributed to J Wadsworth.

At least 55 records · Page 3Linked to original sources
PubMed1991

A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli.

A novel, bis-indolylmaleimide, Ro 31-8425, bearing a conformationally restricted side chain, inhibits protein kinase C isolated from rat brain and human neutrophils with a high degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. It also inhibits phorbol ester-induced intracellular events known to be mediated by protein kinase C (p47 phosphorylation in intact platelets, CD3 and CD4 down-regulation in T-cells). Ro 31-8425 inhibited superoxide generation in human neutrophils activated by both receptor stimuli (formyl-methionyl-leucylphenylalanine, opsonized zymosan, IgG and heat aggregated IgG) and post-receptor stimuli (1,2-dioctanoylglycerol and fluoride). The compound also blocked antigen driven, but not IL-2 induced, T-cell proliferation. These results support a central role for protein kinase C in the activation of the respiratory burst and antigen-driven T-cell proliferation.

Animals↗
PubMed1991

Relation between humoral responses to HIV gag and env proteins at seroconversion and clinical outcome of HIV infection.

OBJECTIVE: To study the contribution of the humoral response to HIV-I at seroconversion to disease outcome after 84 months. DESIGN: A retrospective longitudinal study. SETTING: Two haemophilia centres in the United Kingdom. PATIENTS: 88 Haemophiliac patients infected with HIV-I for whom sera were available from before seroconversion and in whom clinical follow up data were available. RESULTS: Kaplan-Meier survival analysis showed a significant difference between a high titre (greater than 1600) p24 antibody response at seroconversion and prolonged time before the development of HIV related disease (p = 0.0008). In contrast, higher titres of antibody to gp120 at seroconversion (greater than 25,600) correlated with more rapid clinical deterioration (p = 0.025). CONCLUSIONS: The first humoral response to HIV proteins at seroconversion is associated with clinical outcome; patients with an initial low titre antibody response to the gagp24 protein have a significantly faster rate of progression to CDC stage IV disease. Patients with a high titre p24 antibody response progress to AIDS more slowly, and these data provide an explanation why p24 antigenaemia is not universally detected in patients with AIDS. It is unclear whether the association between a strong initial p24 antibody response and slower progression of HIV disease is causal and if so whether it is due to viral or host factors.

Gene Products, gag↗
PubMed1991

Modulation of cellular processes by H7, a non-selective inhibitor of protein kinases.

H7 has been described as a potent inhibitor of protein kinase C (PKC) and has been widely used to investigate the regulatory role of this enzyme in intact cell systems. In this comparative study between H7 and the microbial alkaloid, staurosporine, we found that the former inhibited rat brain PKC and cAMP dependent protein kinase with IC50 values of 18 and 16 microM respectively whereas the latter was a much more potent inhibitor of both kinases with IC50 values of 9.5 nM and 42 nM respectively. H7, at concentrations up to 100 microM, failed to block cellular events induced by phorbol esters, agents which specifically stimulate PKC, yet was a potent inhibitor of IL-2 induced T cell proliferation with an IC50 value of 19 microM. In contrast, staurosporine was a potent inhibitor of both phorbol ester induced p47 phosphorylation in platelet (I50 value = 540 nM) and also CD3 and CD4 down-regulation in T cells (I50 values 200 nM and 50 nM respectively). Staurosporine was also a potent inhibitor of IL-2 induced T cell proliferation I50 value = 9 nM). These results provide a strong argument against the use of H7 to probe for PKC involvement in cellular processes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Simplified single sample 13Carbon urea breath test for Helicobacter pylori: comparison with histology, culture, and ELISA serology.

There is no ideal method for detecting Helicobacter pylori. The 'standard' 13Carbon urea breath test (13C-UBT), which involves collecting eight to 15 breath samples and subsequent costly analysis, was modified by pooling 21 samples of expired breath taken at five minute intervals for 40 minutes into a collecting bag, from which a single 20 ml aliquot was taken and analysed by mass spectrometry. This test was evaluated on 50 patients after routine upper gastrointestinal endoscopy, and results were compared with those from the standard 13C-UBT, bacteriology, ELISA serology, and histology--the latter being taken as the gold standard. H pylori were seen in 34 of 50 (68%) patients (in three it was detected in biopsy specimens from the corpus alone). The modified 13C-UBT was positive (pooled excretion delta 13CO2 greater than 5 per mil) in 31 patients and negative in 19 (three false negative results), specificity was 100% (standard 13C-UBT 94%) and sensitivity 92% (standard 13C-UBT 93%). The modified 13C-UBT had a coefficient of variation within subjects of 3.7%. For the ELISA serology and culture the specificities were both 100%, but the sensitivities were 82% and 68% respectively. The 13C-UBT results correlated with the grade of histological gastritis. The modified 13C-UBT is simpler, cheaper, more reproducible, and provides an easy non-invasive method for the detection of H pylori.

Adult↗
PubMed1991

Children with atopic eczema. I: Clinical response to food elimination and subsequent double-blind food challenge.

The role of foods in the exacerbation of atopic eczema was studied by offering a food elimination diet and subsequent random order, double-blind food challenges to 91 eczematous patients, [49 males and 42 females, median age 4.5 years (range 0.5-15)]. Eczema improved in 49 of 66 (74 per cent) (skin score fall greater than or equal to 3) after stopping cows' milk, eggs and various other foods, with significant decreases in erythema, excoriation, lichenification and extent of eczema. One hundred and ninety-four food challenges were given to 64 patients who had shown objective or subjective improvement. Eczema and associated symptoms were significantly worse after cows' milk and tomato compared with placebo. Egg did not worsen eczema, but 48 per cent of 44 challenges were incomplete, mainly due to hypersensitivity reactions and challenge refusal. The longer a food had been avoided, the less likely was the chance of a positive food reaction. Clinical history did not predict response to dietary manipulation. A standard elimination diet avoiding cows' milk, egg, tomatoes and possibly colours and preservatives should help up to three-quarters of patients, and is easy to implement with the help of a dietician. This diet may be considered in all children with moderate or severe eczema.

Adolescent↗
PubMed1991

Children with atopic eczema. II: Immunological findings associated with dietary manipulations.

A group of 91 children with atopic eczema entered a study where clinical and immunological features were compared before and after a food elimination diet, and after double blind randomized food challenges in which a food was given for several days at a time. Eczema improved significantly during the diet and became worse on food challenges. The clinical outcome of food elimination could not be predicted by the initial skin prick test results, serum immunoglobulins, total or food-specific IgE, or complexed IgG or IgE. There was a tendency for patients whose eczema did not improve after food elimination to have higher initial serum IgG levels, without a corresponding increase in skin infections. The radioallergosorbent test to soy gave a higher result in those who improved on diet. No significant changes in serum or complexed immunoglobulins occurred over the period of food elimination or subsequent food challenge. Results of food challenges could not be predicted by initial serum immunoglobulin levels. A history of spring/summer exacerbations of eczema correlated with positive skin prick tests to silver birch pollen, but not to grass pollen. Serological tests did not help in planning food diets in atopic eczema, and the immunological studies did not delineate any particular mechanism by which foods might exacerbate eczema.

Adolescent↗
PubMed1991

Association of high density lipoprotein cholesterol with plasma lipolytic activity and C-peptide concentration in type 2 diabetes.

In order to assess whether insulin concentration or plasma lipolytic activity has any role in the regulation of HDL cholesterol concentrations in type 2 diabetes, fasting plasma C-peptide and HDL2-cholesterol concentrations and the post-heparin plasma activities of lipoprotein lipase and hepatic endothelial lipase were measured in 148 patients with type 2 diabetes (76 male, 72 female). HDL2-cholesterol was related negatively to hepatic lipase activity in men (r = -0.49, p less than 0.001) and women (r = -0.43, p less than 0.001) and positively to lipoprotein lipase activity in men (r = -0.33, p less than 0.01) and women (r = 0.36, p less than 0.01). A significant inverse relationship was confirmed between C-peptide and the HDL2-cholesterol subfraction in both sexes (men, r = -0.40, p less than 0.001, women r = -0.51, p less than 0.001). This persisted after adjustment for the effects of alcohol intake, mode of hypoglycaemic treatment, plasma glucose and body mass index. The relationship was lost in men and greatly diminished in women when hepatic lipase activity was included in multiple linear regression analysis, whereas the inclusion of lipoprotein lipase activity in the analysis had little effect on the relationship between C-peptide and HDL2-cholesterol. We suggest that hepatic lipase may be partly responsible for the commonly observed inverse relationship between measures of insulin secretion and HDL-cholesterol concentrations. We speculate that this may occur through a direct stimulatory effect of insulin on the enzyme's activity.

C-Peptide↗
PubMed1990

Time-course and relationship of the early changes in renal sodium excretion and aldosterone secretion during dietary sodium restriction in normal man.

1. The fall in renal sodium excretion after dietary sodium restriction is prompt and reproducible. The importance of increased aldosterone secretion during the early phase (within 48 h) of this response is unclear. Using two indirect measures of aldosterone secretion (in urine and saliva), we have tried to relate changes in excretion and concentration of this hormone to renal sodium excretion during the abrupt transition from a normal (approximately 150 mmol/day) or high (260 mmol/day) to a low (5-25 mmol/day) sodium intake in 11 and seven male volunteers, respectively. 2. All subjects showed reduced renal sodium excretion within 36 h of dietary restriction, but the times at which increases in renal aldosterone excretion, saliva aldosterone concentration and plasma renin activity became statistically significant varied widely (8-72 h, 2.5- greater than 62.5 h and less than 4- greater than 38 h for renal aldosterone secretion, saliva aldosterone concentration and plasma renin activity, respectively). Circadian fluctuations in saliva aldosterone concentration were apparent and increased in amplitude during sodium restriction. 3. Urine flow rate tended to increase on the first day of sodium restriction and this reached statistical significance in the group initially on a high sodium intake (64.0 +/- 8.8 to 84.3 +/- 11.2 ml/h, P less than 0.01); although the pattern of urine flow did correlate with plasma arginine vasopressin concentration (r = -0.49, P less than 0.01), there was no significant decrease in mean plasma arginine vasopressin concentration [1.15 (0.92-1.44) to 0.90 (0.72-1.12) pmol/l, P = 0.08; geometric mean and 95% confidence limits].(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Uterine size and endometrial thickness and the significance of cystic ovaries in women with pelvic pain due to congestion.

In a group of 55 women with chronic pain due to pelvic congestion measurement by ultrasound revealed they had a larger uterus and thicker endometrium as compared with a group of normal women matched for age, parity and the presence of polycystic ovaries found on ultrasound scanning. Many women with pelvic congestion (56%) were found on ultrasound to have cystic changes in their ovaries which ranged from a classic polycystic pattern to the appearance of clusters of 4-6 cysts in bilaterally enlarged ovaries. It is suggested that uterine enlargement and thickening of the endometrium are caused by oestrogen, either from the effects on the target organs of an increased concentration or of hypersensitivity to oestrogen.

Adult↗
PubMed1990

Accuracy of ultrasound measurements of female pelvic organs.

Uterine size, endometrial thickness and ovarian volume were measured ultrasonically and the results compared with caliper measurements made shortly afterwards at the time of total hysterectomy and bilateral salpingo-oophorectomy. The results establish the validity of ultrasound measurements. Histological studies also confirmed the diagnosis made with ultrasound of polycystic ovaries in women complaining of pain due to pelvic congestion.

Adult↗
PubMed1990

Liaison psychiatry in general practice: the comprehensive collaborative model.

A model of liaison psychiatry in general practice is described and its impact assessed using data from the Nottingham psychiatric case register. The model incorporates a comprehensive network of general practice psychiatric clinics for both psychiatrists and other mental health professionals, associated with mainly informal liaison with general practitioners and others in the primary care team, and a reduction in psychiatric outpatient clinics. Following the introduction of this model, the proportion of new and referred patients seen in primary care settings rose from 1% to 18% in Nottingham over an 8-year period. Over this period admission rates significantly fell in Nottingham compared with the rest of England and evidence is given that the growth of primary care psychiatry contributed significantly to this reduction.

Adolescent↗
PubMed1990

Alpha-blocker therapy; a possible advance in the treatment of diabetic hypertension--results of a cross-over study of doxazosin and atenolol monotherapy in hypertensive non-insulin dependent diabetic subjects.

Hyperglycaemia, a raised fibrinogen, an increased serum triglyceride and a reduced HDL-cholesterol are common metabolic features of non-insulin dependent diabetes mellitus (NIDDM). Hypertension is frequently associated with NIDDM, however the influence of antihypertensive therapy on these combined factors in the diabetic is at present unclear. In a double-blind placebo-controlled crossover study in 20 stable NIDDM subjects with hypertension, the metabolic effects of 6 weeks' treatment with the alpha-blocker, doxazosin, was compared with treatment with the beta-blocker, atenolol. Similar and significant reductions in BP were produced by both drugs. Significant increases in weight, HbA1, apoprotein B, serum triglyceride and cholesterol/HDL ratio were observed with atenolol therapy. Doxazosin therapy was associated with opposite patterns of changes in fasting glucose, lipids and lipoproteins but only for serum triglyceride was difference between treatments significant. Fibrinogen was not altered by either treatment. Conclusions from this study indicate; 1) adrenergic mechanisms may be an important influence on glucose homeostasis and lipid metabolism in NIDDM and 2) the beta-blocker, atenolol, has a small adverse effect on weight, glycaemic control and the atherogenic lipid profile, whereas the alpha-blocker, doxazosin, has no such effect and may, in part, correct the disturbances of lipoprotein metabolism characteristic of NIDDM.

Adrenergic alpha-Antagonists↗
PubMed1989

Potent selective inhibitors of protein kinase C.

A series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2).

Alkaloids↗
PubMed1989

Expression of results of histamine challenge.

Different aspects of standardization of histamine challenges have been extensively investigated. However, several methods have been used for the actual derivation of the provocation concentration causing a 20% fall in lung function (PC20) from the results of the serial lung function tests (e.g. forced expiratory volume in 1 second [FEV1] ). We have compared these methods on a series of 21 histamine challenges to see if any were systematically inconsistent with the others. The simplest method, with least potential for further error, is interpolation of two points, on either side of the line for 20% fall in lung function, calculated by computer. We conclude that, as this method was consistent with the majority of others, it is the method of choice for deriving the PC20.

Adolescent↗
PubMed1989

The cardiovascular and oncotic effects of albumin infusion in premature infants.

We determined the oncotic and cardiovascular effects of a standardised infusion of human albumin (1.2 g/kg over 2 h as a 20% solution) in 12 premature infants on 18 occasions when hypovolaemia was suspected on clinical grounds. Blood volume increased by a median value of 15.5%, and fell to preinfusion values by 3 h post infusion in all but four cases. Albumin concentration and colloid osmotic pressure rose during infusion and remained raised even when blood volume had fallen to preinfusion levels. Blood pressure rose in 3 cases only and heart rate fell by greater than 5 beats/min in 6 cases. Indices of long- and short-term heart rate variability were unchanged, but blood pressure variability fell in the second hour of infusion (P = 0.03), an effect which was independent of changes in lung inflation. No changes in blood gases or oxygenation occurred during infusion and no evidence of pulmonary oedema was found. There were wide variations in oncotic and cardiovascular responses to the standardised infusion both between and within subjects. When human albumin is infused in this manner some protection against respiration-induced variability in blood pressure can result, but the circulatory response may prove difficult to predict in the individual.

Blood Pressure↗
PubMed1989

Clinical diagnosis from digital displays: preliminary findings of the St Mary's Evaluation Project.

Image quality is a fundamental issue in the introduction of picture archiving and communications systems (PACS), and one that has hitherto been eclipsed by other aspects of the considerable technological challenge facing scientists and manufacturers involved in its development. We conducted a formal evaluation of clinical radiological diagnosis from a commercially available PACS viewing station, using subperiosteal resorbtion in renal osteodystrophy as the test pathological diagnosis, with receiver operating characteristic (ROC) analysis of the results. We conclude that the displayed, digitised images were inferior to film using the apparatus tested and believe that careful, objective clinical evaluation of such systems is of paramount important.

Chronic Kidney Disease-Mineral and Bone Disorder↗