Biomedical subjects
Publications and source records attributed to H M Lewis.
Treatment of psoriasis is rapidly changing with improved understanding of the pathogenesis of the disease. Newer topical preparations such as calcipotriol and immunosuppressive agents such as cyclosporin A and FK506 are having a major impact on the therapy of psoriasis. This article reviews the conventional therapies and newer agents used in the treatment of this common dermatosis.
Twelve healthy volunteers were given single oral doses of bisoprolol 5 mg, 10 mg and 20 mg and atenolol 50 mg and 100 mg in a randomised, placebo-controlled study. The effects of these drugs on beta 2-stimulated hypokalaemia and hyperglycaemia (produced by intravenous terbutaline infusion) were studied. Comparable beta-blockade was achieved with bisoprolol 20 mg, and atenolol 50 mg and 100 mg as measured by attenuation of exercise heart rate. Measurements of areas under or over the curve (AUC and AOC) of hypokalaemic or hyperglycaemic response to terbutaline infusion showed that bisoprolol (10 mg and 20 mg) and atenolol (50 mg and 100 mg) were significantly less beta 1 selective than 5 mg bisoprolol. Furthermore, there was a trend towards decreasing beta 1 selectivity with increasing doses of bisoprolol. Bisoprolol, an effective once daily antihypertensive and antianginal treatment, has comparable beta 1 selectivity to atenolol as measured by metabolic response. At a dose of 5 mg, bisoprolol has a measurable impact on beta 1 receptors but minimal effect on beta 2 receptors.
The effects of steady-state flosequinan, a new peripheral vasodilator, and propranolol on glucose tolerance and plasma lipids in 22 non-insulin-dependent diabetics were investigated in a randomized double-blind placebo-controlled, three-way crossover trial. Flosequinan produced no impairment of glucose tolerance compared with placebo. Propranolol produced significant increases in fasting plasma glucose (P less than 0.01) and increases in the area under the glucose tolerance curve (P less than 0.05) compared to placebo. No significant effects on cholesterol levels were seen on either treatment but triglyceride levels were significantly elevated on propranolol compared with placebo (P less than 0.01). These data suggest that flosequinan, used in therapeutic dosage, has no adverse metabolic effects on the non-insulin-dependent diabetic and this may be an advantage for a drug used in the treatment of hypertension or congestive heart failure.
We have localised atrial natriuretic factor (ANF) in the human kidney by immunocytochemistry and radioimmunoassay. ANF is specifically visualised in the distal convoluted tubule cells and the intercalated cells of the connecting tubules and collecting ducts of the human nephron. The number of immunoreactive cells and tissue values for the peptide were compared between samples from normal kidneys and biopsies obtained from hypertensive patients, in whom the tissue ANF immunoreactivity was found to be reduced. Specific experiments are necessary to establish whether renal ANF is synthesised de novo or captured through endocytosis by the renal tubular cells. The possible functional roles of renal ANF are discussed.
We describe two studies which investigate the beta 2-agonist properties of dilevalol. We have previously demonstrated, by giving an infusion of terbutaline to human volunteers, that beta 2-stimulation causes a rise in plasma glucose and a fall in plasma potassium. These metabolic effects can be prevented by prior beta-blockade. We now show that infusion of dilevalol produces similar, but quantitatively smaller, metabolic effects at a dose which also produces clinically significant beta-blockade, as judged by a fall in exercise heart rate. This adds support to the claim that dilevalol is a non-selective beta-blocker with selective beta 2-agonist activity.
1. The dependence of atrial natriuretic factor on renal dopamine for its renal effects in man was examined in 10 healthy volunteers using the dopa decarboxylase inhibitor carbidopa. 2. Each volunteer attended on two occasions, and received an infusion of atrial natriuretic factor (4 pmol min-1 kg-1) for 60 min after pretreatment with either placebo or carbidopa orally. These were administered in random, double-blind fashion. 3. A similar increase in plasma atrial natriuretic factor concentration was seen after atrial natriuretic factor infusion on both visits. 4. Infusion of atrial natriuretic factor produced a small unsustained rise in urinary dopamine excretion. This increase in urinary dopamine excretion was blocked by carbidopa with no effect on the natriuresis. 5. Urinary guanosine 3':5'-cyclic monophosphate excretion increased in response to the atrial natriuretic factor infusion whether placebo or carbidopa was given. Guanosine 3':5'-cyclic monophosphate, but not dopamine, may be a mediator of the renal response to atrial natriuretic factor in man.
1. The effects of steady state flosequinan, a new vasodilator, and propranolol, on glucose mobilisation, lipolysis and plasma potassium concentration during sub-maximal exercise testing were investigated in a double-blind, randomised, three-way crossover study in 12 healthy volunteers. 2. Plasma glucose, potassium and free fatty acid concentration during and after exercise on flosequinan were similar to those on placebo. Exercise heart rates were 7% (+9.2 beats min-1) higher on flosequinan compared with placebo (P less than 0.05). During exercise on propranolol plasma glucose concentrations were comparable with those on placebo but plasma potassium concentrations were higher (mean increase 0.26 mmol l-1, P less than 0.01) whereas free fatty acid concentrations were lower (mean decrease 0.10 mmol 1-1, P less than 0.01). As expected the heart rate on exercise was 25% less (-35 beats min-1) on propranolol (P less than 0.05). 3. These data suggest that, in contrast to propranolol, flosequinan does not adversely affect the mobilisation of the two major sources of energy during sub-maximal exercise.
The background and aetiology of chronic cough were investigated by comparing 60 children under 6 years with simple cough, 60 children with asthma, and 60 controls. Both cough and asthma were more common in boys and associated with a history of eczema, chest deformity, and skin reactivity to inhaled allergens, but these findings were more prevalent in asthma than cough. House dust mite sensitivity was found in 34 (57%) children with cough, 45 (75%) with asthma, and six (10%) controls. Tests of immunological function showed some high concentrations of IgM in groups with both cough and asthma, but high IgE concentrations, eosinophilia, and lymphocytosis were significant only in asthma. IgG1 and IgG2 concentrations were raised in some children with cough or asthma, but the only low subclass concentrations were of IgG3 observed in the group with cough. Children with simple cough represented a heterogeneous population but many showed evidence of atopy. Major defects of immunity were not observed.
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This two-site immunoradiometric assay (IRMA) for human atrial natriuretic factor (ANF)99-126 in plasma utilizes a mouse monoclonal antibody raised against rat (r) ANF103-125 with specificity directed towards the ring structure of ANF, and a rabbit antiserum to human (h) ANF99-126. The monoclonal antibody is radioiodinated, and the IgG fraction of the antiserum is coated onto wells of a microtiter plate. Plasma or standard hANF99-126 (150 microL) is incubated with the radioligand in coated wells for 24 h. The detection limit is 0.9 pg per well, corresponding to 2 pmol/L, with a working range (CV less than 10%) from 4.5 to 540 pmol/L. Intra- and interassay precision are 7% and 9%, respectively, and the assay is unaffected by plasma matrix. In humans, the IRMA is specific for hANF99-126, the major circulating form of ANF, and does not cross-react with metabolites having deletions at the carboxy terminus. Plasma IRMA values in normal seated subjects were 6.6 +/- 1.5 (SEM) pmol/L and results correlated with those of an extraction RIA (r = 0.81, P less than 0.001).
1. The relationship between plasma immunoreactive atrial natriuretic factor (Ir-ANF) and the urinary excretion of sodium, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and of tissue kallikrein was examined in seven healthy female volunteers. 2. Each volunteer attended on two occasions, a control and a saline infusion day. On the infusion day saline (2 litres, 0.9% NaCl) was administered over 60 min. Measurements of plasma Ir-ANF and urinary excretion of sodium, cyclic GMP and of tissue kallikrein were made at 30 min intervals during the infusion and for 3 h after the infusion. 3. Mean (+/- SEM) urinary sodium excretion increased from a basal value (time 0) of 102 +/- 15 mumo/min to 222 +/- 47 mumol/min 60-90 min from the start of the infusion and thereafter remained significantly elevated (P less than 0.01) above sodium excretion on the control day. 4. In response to saline infusion there was a transient rise in mean (+/- SEM) plasma Ir-ANF from 6.7 +/- 0.8 pmol/l to a peak of 22.5 +/- 3.7 pmol/l at 75 min, falling to 12.7 +/- 1.9 pmol/l at 135 min. The peak plasma Ir-ANF level on the infusion day was significantly elevated (P less than 0.05) above the time-matched measurement on the control day. 5. Similarly, there was a transient rise in mean (+/- SEM) urinary cyclic GMP excretion on the infusion day from 30.9 +/- 4.4 fmol/min to 64.6 +/- 11.4 fmol/min during the 60-90 min collection period, returning to 43.7 +/- 14.5 fmol/min at 210-240 min.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of one hour (40 mmHg) lower body positive pressure on blood pressure, plasma atrial natriuretic factor concentration, and urinary sodium and water excretion was studied in 10 healthy volunteers and seven cardiac transplant recipients. Both groups showed a sustained rise in blood pressure and plasma atrial natriuretic factor concentration. The healthy volunteers had a diuresis during the period of lower body positive pressure and a small natriuresis in the subsequent hour. In contrast, lower body positive pressure had no significant effect on urinary sodium and water excretion in the cardiac transplant group. The data suggest that cardiac innervation is not important as a mediator of the haemodynamic response to lower body positive pressure but is necessary for the renal response. Furthermore, small physiological rises in plasma atrial natriuretic factor concentrations do not cause a brisk natriuresis as has been reported with pharmacological plasma concentrations.
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The interaction between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone (RAA) system was studied in 6 healthy volunteers using the angiotensin-converting-enzyme (ACE) inhibitor, captopril. Each volunteer received, on separate occasions in random order, 48 hours treatment with a) low-dose captopril (6.25 mg twice daily), b) 'high-dose' captopril (25 mg twice daily) and c) placebo prior to an infusion of synthetic human ANP (99-126). Resting plasma ANP levels were significantly (P less than 0.01) higher on treatment with 'high-dose' captopril when compared with low-dose captopril or placebo. 'High-dose' captopril reduced mean arterial blood pressure (BP) and significantly (P less than 0.01) reduced the natriuretic response to the human ANP infusion. These results support the hypothesis that ACE is involved in ANP metabolism. The reduced renal response to ANP during treatment with captopril may reflect the dependence of ANP on adequate renal perfusion pressure and angiotensin II levels to exert its natriuretic effect.
The dihydrolipoamide acetyltransferase component (E2p) of the pyruvate dehydrogenase complex of Escherichia coli contains three highly homologous sequences of about 100 residues that are tandemly repeated to form the N-terminal half of the polypeptide chain. All three sequences include a lysine residue that is a site for lipoylation and they appear to form independently folded functional domains. These lipoyl domains are in turn linked to a much larger (about 300 residues) subunit-binding domain of the E2p chain that aggregates to form the octahedral inner core of the complex and also contains the acetyltransferase active site. In order to investigate whether individual lipoyl domains play different parts in the enzymic mechanism, selective deletions were made in vitro in the dihydrolipoamide acetyltransferase gene (aceF) so as to excise one or two of the repeating sequences. This was facilitated by the high degree of homology in these sequences, which allowed the creation of hybrid lipoyl domains that closely resemble the originals. Pyruvate dehydrogenase complexes incorporating these genetically reconstructed E2p components were purified and their structures were confirmed. It was found that the overall catalytic activity, the system of active site coupling, and the ability to complement pyruvate dehydrogenase complex mutants, were not significantly affected by the loss of one or even two lipoyl domains per E2p chain. No special role can be attached thus far to individual lipoyl domains. On the other hand, certain genetic deletions affecting the acetyltransferase domain caused inactivation of the complex, highlighting particularly sensitive areas of that part of the E2p chain.
The nucleotide sequence of a 1980-base-pair segment of DNA, containing the lpd gene encoding the lipoamide dehydrogenase component (E3) of the pyruvate dehydrogenase complex of Escherichia coli K12, has been determined by the dideoxy chain-termination method. The lpd structural gene comprises 1419 base pairs (473 codons, excluding the initiating AUG codon). It is preceded by a good promoter and an excellent ribosome binding site and it ends with a typical rho-independent terminator sequence. The results confirm that the lpd gene is an independent gene linked to, but not part of, the ace operon that encodes the E1 and E2 components of the pyruvate dehydrogenase complex. The location and transcriptional polarity of the lpd gene relative to the restriction map of the corresponding region of DNA, are completely consistent with previous genetic and post-infection labelling studies. The composition, Mr (50554 or 51274 if the FAD cofactor is included), amino-terminal sequence and carboxy-terminal sequence predicted from the nucleotide sequence are in excellent agreement with previous studies on the purified enzyme. The enzyme also exhibits a remarkable degree of sequence homology with peptides of the pig heart enzyme and with other pyridine nucleotide disulphide oxidoreductases whose sequences have been defined: human erythrocyte glutathione reductase and plasmid-encoded mercuric reductase.
The nucleotide sequence of the aceF gene, which encodes the dihydrolipoamide acetyltransferase component (E2) of the pyruvate dehydrogenase complex of Escherichia coli K12, has been determined using the dideoxy chain-termination method. The aceF gene comprises 1887 base pairs (629 codons excluding the initiation codon AUG); it is preceded by a short intercistronic segment of 14 base pairs containing a good ribosomal binding site, and it is followed closely by a potential rho-independent terminator. The results extend by 1980 base pairs the previously sequenced segment of 3780 base pairs containing the structural gene (aceE) of the pyruvate dehydrogenase component (E1) and they confirm that aceE and aceF are the proximal and distal genes of the ace operon. The amino terminus, carboxy-terminal sequence and amino acid composition of the acetyltransferase subunit predicted from the nucleotide sequence are in excellent agreement with previous studies with the purified protein. The predicted molecular weight (Mr = 65959) confirms experimental values derived from sedimentation equilibrium analysis and indicates that the higher values (78000-89000) that have been reported are due to unusual features of the protein that lead to anomalous mobilities during sodium dodecyl sulphate/polyacrylamide gel electrophoresis and in gel filtration. The primary structure fully supports conclusions, based on limited tryptic proteolysis, that the acetyltransferase subunit possesses two heterologous domains: the lipoyl domain and the subunit binding and catalytic domain. The lipoyl domain corresponds to the amino-terminal segment of the protein. It is acidic and contains three remarkably homologous repeating units of approximately 100 amino acids, each possessing a potential lipoyl binding site and a region that is characteristically rich in alanine and proline residues. The subunit binding and catalytic domain occupies most of the residual polypeptide in the carboxy-terminal segment.