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Biomedical subjects

K Pollock

Publications and source records attributed to K Pollock.

At least 19 recordsLinked to original sources
PubMed2001

Characteristics of arterial wall shear stress which cause endothelium-dependent vasodilatation in the anaesthetized dog.

1. The effects of changes in the mean and amplitude of arterial wall shear stress on endothelium-dependent arterial dilatation of the iliac artery of the anaesthetized dog were examined. 2. Changes in the mean and amplitude of blood flow and wall shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and the stimulation of the left ansa subclavia. Changes in the diameter of a segment of the iliac artery with the endothelium intact, relative to a segment with no endothelium, were used as an index of the release of nitric oxide. 3. The increase in mean blood flow was from 84 +/- 12 to 527 +/- 53 ml min-1 and in amplitude was from 365 +/- 18 to 695 +/- 38 ml min-1 (means +/- S.E.M.). The increase in mean wall shear stress was from 1.78 +/- 0.30 to 7.66 +/- 1.01 N m-2 and in amplitude was from 7.37 +/- 0.46 to 13.9 +/- 2.00 N m-2 (means +/- S.E.M.). 4. Increases in mean shear stress caused an increase in the diameter only of the section of artery with endothelium; the slope of the relationship was 0.064 +/- 0.006 mm N-1 m2 (mean +/- S.E.M., P < 0.001); changes in the amplitude of shear stress did not cause an increase in diameter. Changes in both the mean and amplitude of shear stress had no significant effect on the diameter of the section of artery with no endothelium. 5. These findings coupled with the known anti-atheroma effects of nitric oxide and the effect of shear stress on cell adhesion and platelet aggregation offer a possible explanation for the disposition of atheroma in those parts of the arterial system which have low mean and high amplitude of wall shear stress.

Acetylcholine↗
PubMed2001

Analysis of cellular adhesion by microarray expression profiling.

Microarrays of oligonucleotides or cDNAs can be used to establish the expression profiles of numerous genes in a single experiment. We have established a microarray platform to identify genes in a number of different pathological conditions, particularly those with an inflammation component. This platform utilised the output of an eosinophil sequencing project in which 1069 sequences were identified that were not represented in the public domain. An eosinophil model cell line, AML14.3D10, was used to investigate cell adhesion. The transcription profile of adhered and non-adhered AML 14.3D10 cells was shown to be both technically and biologically reproducible. A number of genes were found differentially expressed in the adhered vs. non-adhered populations. In the adhered population, the expression of these genes was restricted compared to brain, lung, kidney and especially bone marrow. However, the differentially regulated genes were not among those genes most restricted to eosinophils. We discuss the implications of transcription profiling on gene annotation and its potential utility for the identification of targets for drug intervention.

Base Sequence↗
PubMed2001

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Administration, Oral↗
PubMed2000

Strategies for reducing the prescribing of proton pump inhibitors (PPIs): patient self-regulation of treatment may be an under-exploited resource.

Escalating costs of proton pump inhibitor (PPI) prescribing are a source of increasing concern. To reduce costs, GPs in the UK have been coming under pressure to restrict PPI prescribing in primary care, e.g. by raising the prescribing threshold for new patients, and encouraging established patients to accept a reduced dose, if not stop taking PPIs altogether. The need to reduce prescribing costs impacts on patients by redefining, i.e. reducing, the boundaries of clinical need for which PPI prescribing is deemed appropriate. This may be rationalised by the assumptions that much existing prescribing is inappropriate, is applied to relatively minor and trivial afflictions, and that patients put pressure on their doctors to initiate prescribing of PPIs, after which they are very reluctant to give them up. The research involved extended interviews to elicit GP and patient views and experience of PPI prescribing. A particular focus was a comparison of the views of patients and GPs, and the understanding and articulation of the patient perspective on PPIs, which has been largely absent from the discussion to date. The research identified six distinct strategies used by GPs in their efforts to reduce PPI prescribing. Contrary to what GPs often assumed to be the case, patients were generally quite receptive to changes to their medication, provided they had the security of knowing that their original prescription would be restored if necessary. Most doctors assessed their rationing strategies as having some impact, but acknowledged the difficulties in achieving a significant and sustained reduction in PPIs. In the study sample nearly half of the patients who had experienced a prescribing switch or step down had drifted back to their former brand, and, especially, higher dose. However, far from being overly and unreflectively dependent on PPIs, patients were often keen to reduce their medicine taking to a minimum. A number of respondents had taken the initiative in experimenting to find the lowest effective dose of PPIs required to control their symptoms. GPs varied in their attitudes to this form of treatment self-management, but less than half actively encouraged patients to regulate their treatment in this way. Our findings suggest that there is considerable scope for encouraging patients to self-regulate with PPIs, and that many patients would be willing to do this if the practice was sanctioned by their doctors. The anticipated benefits of increased self-regulation include an overall reduction in PPI prescribing and associated costs, and an increase in patient autonomy and control which is in line with the concordance model of the ideal relationship between patients and doctors.

Adult↗
PubMed2000

Crystallization and preliminary X-ray analysis of shikimate dehydrogenase from Escherichia coli.

Shikimate dehydrogenase from Escherichia coli has been crystallized by the vapour-diffusion method using ammonium sulfate as a precipitant. Mass spectrometry confirmed the purity of the enzyme and dynamic light scattering was used to find the appropriate additives to yield a monodisperse enzyme solution. The crystals are monoclinic, space group C2, with unit-cell parameters a = 110.0, b = 139.8, c = 102.6 A, beta = 122.2 degrees (at 100 K). Native crystals diffract to 2.3 A in-house on a rotating-anode X-ray source. The asymmetric unit is likely to contain four molecules, related by 222 symmetry, corresponding to a packing density of 2.86 A(3) Da(-1).

Alcohol Oxidoreductases↗
PubMed1998

Inhibition of sCD23 and immunoglobulin E release from human B cells by a metalloproteinase inhibitor, GI 129471.

Soluble CD23 (sCD23) has been proposed to play an important role in the up-regulation of immunoglobulin E (IgE) synthesis. Production of sCD23 is dependent on the proteolytic cleavage of membrane CD23, but the protease(s) involved in this process remain unknown. Preliminary data, obtained by testing a panel of protease inhibitors, suggested that this enzyme may be a zinc-dependent metalloproteinase. Therefore, we investigated the effect of a standard hydroxamate-type Zn2+ metalloproteinase inhibitor (GI 129471) on both sCD23 and IgE release from human tonsillar B cells, stimulated with interleukin-4 (IL-4) and anti-CD40. Incubation of cells for 3 days with GI 129471 inhibited the production of sCD23 with an IC50 of 602 nm+/-3 nm (n=3), but by 14 days the activity of the compound against sCD23 had decreased by greater than threefold (IC50 2+/-0.26 microM; n=3). On the other hand, GI 129471 caused a potent inhibition of IgE production, with no apparent loss of activity over the culture period (14 days: IC50 250 nm+/-72 nm; n=3). Time-course studies showed that, despite loss of activity against sCD23, inhibition of sCD23 production early in the culture was able to cause a potent and long-lasting inhibitory effect on IgE. Furthermore, we also showed that the activity of GI 129471 is selective for IgE, as no effect was seen on immunoglobulin G1 (IgG1) or IgG4 production at test concentrations as high as 10 microM. These results support the hypothesis that metalloproteinases may be involved in the proteolytic cleavage of CD23 and subsequent regulation of IgE synthesis. Inhibition of the protease(s) responsible for such cleavage may be of value in the treatment of allergic disease.

B-Lymphocytes↗
PubMed1996

Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low-affinity' phosphodiesterase 4 conformer.

1. We have investigated the inhibitory effects of RP 73401 (piclamilast) and rolipram against human monocyte cyclic AMP-specific phosphodiesterase (PDE4) in relation to their effects on prostaglandin (PG)E2-induced cyclic AMP accumulation and lipopolysaccharide (LPS)-induced TNF alpha production and TNF alpha mRNA expression. 2. PDE4 was found to be the predominant PDE isoenzyme in the cytosolic fraction of human monocytes. Cyclic GMP-inhibited PDE (PDE3) was also detected in the cytosolic and particulate fractions. Reverse transcription polymerase chain reaction (RT-PCR) of human monocyte poly (A+) mRNA revealed amplified products corresponding to PDE4 subtypes A and B of which the former was most highly expressed. A faint band corresponding in size to PDE4D was also observed. 3. RP 73401 was a potent inhibitor of cytosolic PDE4 (IC50: 1.5 +/- 0.6 nM, n = 3). (+/-)-Rolipram (IC50: 313 +/- 6.7 nM, n = 3) was at least 200 fold less potent than RP 73401. R-(-)-rolipram was approximately 3 fold more potent than S-(+)-rolipram against cytosolic PDE4. 4. RP 73401 (IC50: 9.2 +/- 2.1 nM, n = 6) was over 50 fold more potent than (+/-)-rolipram (IC50: 503 +/- 134 nM, n = 6) ) in potentiating PGE2-induced cyclic AMP accumulation. R-(-)-rolipram (IC50: 289 +/- 121 nM, n = 5) was 4.7 fold more potent than its S-(+)-enantiomer (IC50: 1356 +/- 314 nM, n = 5). A strong and highly-significant, linear correlation (r = 0.95, P < 0.01, n = 13) was observed between the inhibitory potencies of a range of structurally distinct PDE4 inhibitors against monocyte PDE4 and their ED50 values in enhancing monocyte cyclic AMP accumulation. A poorer, though still significant, linear correlation (r = 0.67, P < 0.01, n = 13) was observed between the potencies of the same compounds in potentiating PGE2-induced monocyte cyclic AMP accumulation and their abilities to displace [3H]-rolipram binding to brain membranes. 5. RP 73401 (IC50: 6.9 +/- 3.3 nM, n = 5) was 71 fold more potent than (+/-)-rolipram (IC50: 490 +/- 260 nM, n = 4) in inhibiting LPS-induced TNF alpha release from monocytes. R-(-)-rolipram (IC50: 397 +/- 178 nM, n = 3) was 5.2-fold more potent than its S-(+)- enantiomer (IC50: 2067 +/- 659 nM, n = 3). As with cyclic AMP, accumulation a closer, linear correlation existed between the potency of structurally distinct compounds in suppressing TNF alpha with PDE4 inhibition (r = 0.93, P < 0.01, n = 13) than with displacement of [3H]-rolipram binding (r = 0.65, P < 0.01, n = 13). 6. RP 73401 (IC50: 2 nM) was 180 fold more potent than rolipram (IC50: 360 nM) in suppressing LPS (10 ng ml-1)-induced TNF alpha mRNA. 7. The results demonstrate that RP 73401 is a very potent inhibitor of TNF alpha release from human monocytes suggesting that it may have therapeutic potential in the many pathological conditions associated with over-production of this pro-inflammatory cytokine. Furthermore, PDE inhibitor actions on functional responses are better correlated with inhibition of PDE4 catalytic activity than displacement of [3H]-rolipram from its high-affinity binding site, suggesting that the native PDE4 in human monocytes exists predominantly in a 'low-affinity' state.

Benzamides↗
PubMed1990

Stimulus-response coupling in FMLP-stimulated U937 monocytes: effect of differentiation on Gi2 expression.

The effect of differentiation on FMLP-stimulated InsP production and G-protein expression was investigated in U937 monocytes. FMLP (0.01-10 microM) stimulated [3H]InsP production in dimethyl sulphoxide-differentiated, but not in immature, U937 cells. Ionomycin (1 and 10 microM) stimulated [3H]InsP production equally well in both cell types. The FMLP response was blocked by pertussis toxin (100 ng/ml for 4 h) which catalysed [32P]ADP ribosylation of a 40 kDa 'Gi-like' G-protein alpha subunit in these cells. This protein was also identified immunologically using anti-peptide antibodies that detect 'Gi-like' alpha subunits (SG2) or Gi2 alpha specifically (LE2). With LE2 a 5-fold increase in Gi2 alpha levels was seen following differentiation of the cells, suggesting that FMLP receptor expression is accompanied by an increase in the G-protein with which these receptors interact.

Adenosine Diphosphate Ribose↗
PubMed1990

Leukotriene D4 induced calcium changes in U937 cells may utilize mechanisms additional to inositol phosphate production that are pertussis toxin insensitive but are blocked by phorbol myristate acetate.

DMSO differentiated U937 cells responded to 10(-6) M LTD4, LTB4 and FMLP with an increase in both InsP formation and [Ca2+]i. FMLP caused a greater rise in InsPs than either LTD4 or LTB4, which were equivalent. LTD4, however, caused a greater increase in [Ca2+]i than LTB4 (4-fold) or FMLP. The FMLP [Ca2+]i and InsP responses were abolished by pertussis toxin (100 ng/ml for 4 h) but were unaffected by PMA (10(-7) M for 3 min). In contrast, the LTD4 [Ca2+]i and InsP responses were reduced by only 50% by pertussis toxin, whilst PMA reduced the [Ca2+]i and InsP responses to LTD4 by 75 and 30%, respectively. These results suggest that mechanisms additional to InsP formation exist for mediating LTD4 evoked increases in [Ca2+]i.

Calcium↗
PubMed1989

Urological history-taking and management recommendations by microcomputer.

A system has been developed to acquire a complete urological history using an Apple microcomputer. The system can ask up to 300 multiple choice questions which the patient answers using a light pen. The questions are grouped into blocks for urological symptoms and complicating factors. A printout summarises the history and the recommended further investigations. A copy of this is given to the patient and the referring doctor. The clinician discusses the printout and proposed investigations with the patient. The system has been tested against experienced clinicians and the results are presented. The computer system was evaluated for 26 patients and was found to record all of the important information. The system is now in regular use in the out-patient clinic as the first part of the diagnostic work-up in suitable referrals. This system has shortened waiting times for first appointments. To date 261 patients have used the system. The consultant urologist continues his practice of reading all referral letters and allocating priorities. Conditions requiring immediate physical examination (e.g. testicular swelling) are not suitable for this type of approach.

Diagnosis, Computer-Assisted↗
PubMed1988

On the nature of social stress: production of a modern mythology.

In recent decades there has been increasing interest in the subject of stress and a proliferation of research into the contribution of stress as a cause of illness. This association has been widely popularized and now has an established position within the body of popular ideas about health and illness. Nevertheless, very little has been confidently established about the relationship between stress and illness. The precise nature of stress itself eludes definition and there is no consensus as to what it encompasses. There has been a confusion of the models of stress developed in the laboratory and those applied to society. Early laboratory research was modelled on 'mechanical' images of stress taken from contemporary physics and engineering. Since then the stress theory has been heavily psychologised, although it still relies for its validation on the physiological models with which it is fundamentally non-comparable. It is argued that stress is not something naturally occurring in the world, but a manufactured concept which has by now become a 'social fact'. As such it has direct implications for the ways in which people perceive their world and act within it. Stress has increasingly come to be regarded as an integral part of everyday experience. Although much of the attractiveness of the stress theory derives from its seeming to reduce the arbitrariness of suffering, it also carries with it a significant ideological component. This can serve as a means of organising and expressing a variety of ideas about the social order relating, for example, to issues of individual autonomy and responsibility, or to the ways in which society might be perceived as dangerous, repressive or pathogenic.

Humans↗
PubMed1988

Human T-cell antigen receptor (TCR) delta-chain locus and elements responsible for its deletion are within the TCR alpha-chain locus.

Individual T cells express the CD3 molecule in association with alternative gamma delta or alpha beta heterodimeric T-cell receptors (TCRs). T-cell precursors and occasional gamma delta-expressing T cells in humans possess an unexpected 2.0-kilobase (kb) mRNA in which a tandemly repeated motif, TEA (T early alpha), has been spliced to the constant (C alpha) region. Long-range pulsed-field gel mapping as well as molecular cloning showed that TEA is located immediately 5' to the most upstream joining (J alpha) segment of the TCR alpha-chain locus. The TCR delta-chain locus is immediately 5' to TEA, and diversity (D delta) gene segments, J delta, C delta, and TEA are linked within 35 kb. The human TCR delta locus conserves a 12/23-base-pair (bp) spacer paradigm in which J delta possesses a 12-bp and V delta a 23-bp spacer, while the D delta segments have a 12 bp-D delta-23 bp spacer motif. Considerable TCR delta diversity can be generated despite the predominant use of one V delta and one J delta segment. Two D delta segments, D delta 1 and D delta 2, are 9 and 13 bp long, are frequently recombined as D delta 1-D delta 2, and reveal exonucleolytic trimming with extensive N-segment addition. A gamma delta clonal T cell possessed an effective VDDJ delta rearrangement and an intermediate DDJ delta rearrangement, arguing that the TCR delta locus displays allelic exclusion. Specific rearranging elements that delete the delta locus, delta Rec and psi J alpha, were mapped and found to separate the delta locus from the alpha locus. The delta locus including D delta 1-D delta 2-J delta 1-C delta-TEA was deleted in mature, alpha beta-expressing T cells, whereas V delta 1 was frequently retained. The location of the delta locus within the alpha locus may necessitate an exclusive choice between delta or alpha expression.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1977

Effects of erythrocyte lysate and erythrocyte-conditioned medium on erythroid cells in vitro.

A component of erythrocyte-conditioned medium has been shown to inhibit the incorporation of tritiated thymidine into erythroblasts from fetal mouse liver, proliferating in vitro. This component, however, has no detectable effect on the growth of colonies of erythroid cells stimulated to grow in viscous culture media by the hormone erythropoietin. Erythrocyte lysate and preparations of haemoglobin derived from the lysate increase the number and size of the colonies growing in vitro. Results are discussed in terms of possible control mechanisms in erythropoiesis.

Animals↗