Biomedical subjects
Publications and source records attributed to L Fitzgerald.
A series of 4-aryl-2-(N-ethylanilino)pyrimidines has been synthesized as corticotropin-releasing hormone (CRH) inhibitors. The effect of substitution on each aromatic ring on receptor binding was investigated.
The Suzuki reaction has been used to synthesize a variety of aryl-substituted heterocyclic antagonists of the CRH1 receptor. Examples with several different heterocyclic cores are potent CRH receptor ligands.
Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.
Structure-activity studies around the 4-position of 2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists suggest that there is a large lipophilic cavity in the rat CRF receptor, which can accommodate a wide variety of substituents at this position in contrast to the steric constraints observed for other positions on the 2-anilinopyrimidine core. The chemical syntheses and biological activities of 2-anilinopyrimidine CRF antagonists with carbon-linked substituents at the 4-position are reported. Significant improvements in rat pharmacokinetic parameters were achieved relative to those for the lead structure. While the lead compound 1 (rCRF Ki = 44 nM) afforded no detectable rat plasma levels after intraperitoneal (i.p.) or oral (p.o.) dosing, compounds 3-3 (rCRF Ki = 16 nM) and 3-4 (rCRF Ki 59 nM) gave high rat plasma levels at 30 mg/kg (i.p., p.o.) (Cmax = 1389 nM and 8581 nM (i.p.) respectively; Cmax = 113 nM and 988 nM (p.o.), respectively). Furthermore 3-3 and 3-4 had superior bioavailabilities at these doses (59 and 46% (i.p.), respectively; 2 and 10%, (p.o.), respectively).
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There has been growing interest in recent years in the application of the principles of evidence-based medicine (EBM), although implementation is complex. Scientific, organisational, and behavioural factors all combine to shape clinical behaviour change. Case study based qualitative data are presented which illuminate such processes within one clinical setting (elective orthopaedics), drawn from a larger study. It is suggested that (1) there are alternative models of what constitutes "evidence" in use; (2) scientific knowledge is in part socially constructed; and (3) clinical professionals retain a monopoly of technical knowledge. The implication is that there may be severe obstacles to the rapid or broad implementation of EBM.
This paper is based on an empirical study of attempts to achieve change in clinical behaviour across a United Kingdom National Health Service (NHS) Health Authority (HA). We suggest that the evidence based medicine (EBM) movement underpinning such attempts is premised upon a highly rationalistic conception of change. Here the generation and implementation of research findings into clinical practice is understood as movement between discrete entities. Drawing upon poststructural philosophy, social studies of science and technology, social anthropology, and gender studies, we challenge such linear perspectives through a more immanent alternative. We conceive of change as movement within indeterminate or ambiguous relationships. We then proceed to discuss the implications of this modality for the management of clinical behaviour change.
Focuses on the critical role played by professionals in the management of healthcare institutions in the UK and Canada. Using empirical data, examines the structural models of clinical management, the roles of clinical managers and their relationships with colleague professionals. Compares the approaches taken in the UK and Canada, and explores issues of context, history and relative power. Questions the extent to which professionals are losing autonomy to other professions and management. In particular examines whether the sharing of power inter-professionally may lead to greater, overall collective professional autonomy. Develops themes of the contextual influences on the process of change, and whether professionals are more effectively managed by internal or external processes of control.
OBJECTIVE: Despite current recommendations calling for regular screening flexible sigmoidoscopies over the age of 50, only a small percentage of the population have regular examinations. Improving patient tolerance of flexible sigmoidoscopies could therefore increase patient compliance with these recommended guidelines. The aim of this study was to determine whether audio and visual stimulation reduces discomfort during flexible sigmoidoscopy and whether the effects of the stimulation are secondary to distraction. METHODS: A total of 37 patients undergoing routine screening flexible sigmoidoscopy were randomized to receive no intervention, audio stimulation alone, or audio and visual stimulation. Patient discomfort ratings and affect states were measured prior to and immediately following flexible sigmoidoscopy using a visual analogue scale and the Stress Symptom Ratings (SSR) ratings. RESULTS: Patients receiving audio and visual intervention had lower abdominal discomfort ratings (7.1 +/- 1.4) than patients receiving audio stimulation (9.5 +/- 1.3) or no intervention (10.8 +/- 1.6) (p < 0.05). Patients receiving audio and visual intervention also had higher arousal (7.3 +/- 0.4) and attention (9.2 +/- 0.2) ratings than patients receiving no intervention (6.1 +/- 0.4 and 6.2 +/- 0.7, respectively) (p < 0.05). Anxiety and anger ratings, on the other hand, were significantly lower in patients receiving audio and visual intervention (2.5 +/- 0.4, 1.4 +/- 0.3, respectively) than patients receiving no intervention (4.4 +/- 0.6, 3.6 +/- 0.7). CONCLUSION: Audio and visual stimulation reduces abdominal discomfort associated with flexible sigmoidoscopy. This effect appears to be due to distraction.
In the current study, we investigated the mechanism by which protein kinase C (PKC) regulates the expression of beta1-adrenergic receptor (beta1AR) mRNA in rat C6 glioma cells. Exposure of the cells to 4beta-phorbol-12-myristate-13-acetate (PMA), an activator PKC, resulted in a down-regulation of both beta1AR binding sites and mRNA levels in a time- and concentration-dependent manner. This effect was not observed with phorbol esters that do not activate PKC and was blocked by bisindolylmaleimide, a specific PKC inhibitor. Activation of PKC did not reduce the half-life of beta1AR mRNA but significantly decreased the activity of the beta1AR promoter, as determined by reporter analysis. A putative response element, with partial homology to a consensus cAMP response element, was identified by mutation analysis of the promoter at positions -343 to -336, relative to the translational start site. Mutation of this putative regulatory element, referred to as a beta1AR-PKC response element, completely blocked the PKC-mediated down-regulation of beta1AR promoter activity. Gel mobility shift analysis detected two specific bands when C6 cell extracts were incubated with a labeled DNA probe containing the beta1AR-PKC response element sequence. Formation of one of these bands was inhibited by an oligonucleotide probe containing a consensus CRE and disrupted by an antibody for cAMP response element binding protein. Based on these studies, we propose that the PKC-induced down-regulation of beta1AR gene transcription in C6 cells is mediated in part by a cAMP response element binding protein-dependent mechanism acting on a novel response element.
Bovine adenovirus type 2 (BAV2) is a medium size double-stranded DNA virus which infects both bovine and ovine species, resulting in mild respiratory and gastrointestinal disorders. To better understand the virus and its growth characteristics in Madin-Darby bovine kidney (MDBK) cells, we have cloned and sequenced the extreme right-end segment of the BAV2 genome (90.5-100 map units). Analysis of the nucleotide sequence revealed 40 potential open reading frames (ORFs) with coding capacity for polypeptides that are 25 or more amino acid (aa) residues long. Six of these ORFs encode polypeptides that show homology to well-characterized early region 4 (E4) proteins of human adenovirus type 2 (Ad2) and Ad12. ORF1 has the potential to encode a 114 aa long polypeptide that is 54% homologous to the E4 14kDa protein of Ad2. ORF2 encodes a 78 aa long polypeptide that exhibits 40% homology to the E4 13 kDa protein of Ad2. ORFs 3-6 encode polypeptides that have homology to the E4 34 kDa protein encoded by ORF6 of Ad2 and Ad12. ORFs 3, 4 and 5 encode 128, 96 and 31 aa long polypeptides, respectively. The 128-aa polypeptide exhibits 59% homology, while the 96 and 31 aa long polypeptides exhibit 61% and 70% homology to the E4 34 kDa protein, respectively. ORF6 has the potential to encode a 57 aa long polypeptide that has 67% homology to the E4 34 kDa protein of Ad2 and 50% homology to the E4 34 kDa protein of Ad12.
To form distant metastases, tumour cells must stabilize adhesive interactions that prevent detachment at secondary sites. Primary receptor-ligand interactions alone may not maintain prolonged adhesive contacts without secondary events that lead to adhesion stabilization. Computerized imaging methods enable us to examine various substrates for: (i) the wall shear adhesion threshold (WSAT), a measure of the dynamic adhesive potential of tumour cells; (ii) the number of tumour cells that adhered; and (iii) the adhesion stabilization lag time (ASLT) or length of time required for tumour cells to stabilize adhesive contacts capable of withstanding high wall shear force (up to 100 dynes/cm2). The relative WSAT ratios found were: wheat germ agglutinin (WGA) > laminin > fibronectin > vitronectin > collagen I > collagen IV > von Willebrand factor (vWF) (the greater the shear rate the higher the adhesive potential). The relative stabilization ratios found were as follows: laminin < fibronectin < vitronectin < collagen IV < collagen I < vWF < WGA (shorter times correlate with greater stabilization potential). Stabilization data using fibronectin as a substrate correlated the best with metastatic potential. Using three melanoma lines of different metastatic potential semiquantitative reverse transcriptase-polymerase chain reaction (PCR) showed a two- to four-fold increase in alpha1, alpha3, alpha4, alpha5, alpha6, and ICAM-1 in the highly metastatic 70W cells compared to the MeWo and non-metastatic 3S5 melanoma cells. There were no differences in alphav, beta1 and beta3 levels among the three melanoma lines, and PCR products for alphaIIb, alpha2, CD36, or ICAM-2 were not detected. The 70W cells also had higher levels of alphax and beta2 (CD11/CD18 and p150 leukocyte antigen) than either the MeWo or 3S5 cells. The data indicate that melanoma cells exhibit differences in the adhesion properties under fluid shear and differences in the expression of adhesion components that correlate with their metastatic potential.
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The purpose of this randomized controlled study was to assess the haemodynamic effects, safety and tolerability in acute myocardial infarction (AMI) of one month of oral captopril, one month of oral isosorbide mononitrate and 24 h of intravenous magnesium. It was carried out in four United Kingdom and six Polish hospitals in consecutive phases: oral captopril vs oral mononitrate vs placebo were compared among 400 patients in a 'three-way' study; and then oral captopril vs placebo and oral mononitrate vs placebo were compared among 474 patients in '2 x 2' and '2 x 2 x 2' factorial studies (with 208 patients in the latter study also randomized between intravenous magnesium and open control). The factorial studies differed from the three-way study in that one group of patients was allocated both oral captopril and oral mononitrate, a higher maintenance dose of captopril was used (following the same initial dose), and once daily controlled-release mononitrate was used. In the three-way study, the mean of the lowest systolic blood pressures recorded during the first 4 h after randomization were (mmHg +/- standard error): 104 +/- 2 captopril vs 105 +/- 1 mononitrate vs 112 +/- 2 placebo (P < 0.001 for captopril or for mononitrate vs placebo), and in the factorial studies were 105 +/- 1 captopril vs 110 +/- 1 placebo (P < 0.01) and 106 +/- 1 mononitrate vs 108 +/- 1 placebo (NS). There was an excess of hypotension recorded among patients allocated active treatment (captopril > mononitrate > placebo) and there was a small, but significant, excess of cardiogenic shock with captopril compared with control in the factorial study. However, in these studies, neither captopril nor mononitrate were associated with any overall increase in the incidence of hypotension considered severe enough to lead to treatment being stopped. No other serious complications were observed, and compliance with study tablets at hospital discharge was not significantly different between the active and placebo groups. Patients allocated magnesium in the 2 x 2 x 2 factorial study had a slightly lower mean systolic blood pressure just after the initial 15 min bolus injection (126 +/- 2 magnesium vs 134 +/- 3 control; P < 0.05) but there were no significant differences during the subsequent 24 h maintenance infusion period. Apart from some facial flushing, magnesium did not appear to be associated with any complications.(ABSTRACT TRUNCATED AT 400 WORDS)
Examines the issue of involving clinicians in management and the management processes. Considers the effect of the changing context of practice and the pressures that are imposed on the medical profession by this involvement.
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