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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 163 records · Page 9Linked to original sources
PubMed1993

Protein domains governing interactions between E2F, the retinoblastoma gene product, and human papillomavirus type 16 E7 protein.

Human papillomaviruses (HPVs) are the etiological agents for genital warts and contribute to the development of cervical cancer in humans. The HPV E7 gene product is expressed in these diseases, and the E7 genes from HPV types 16 and 18 contribute to transformation in mammalian cells. Mutation and deletion analysis of this gene suggests that the transforming activity of the protein product resides in the same domain as that which is directly involved in complex formation with the retinoblastoma gene product (pRB). This domain is one of two conserved regions (designated CRI and CRII) shared by E7 and other viral oncoproteins which bind pRB, including adenovirus E1A protein. Binding of HPV type 16 E7 protein to pRB has previously been shown to affect pRB's ability to bind DNA and to form complexes with other cellular proteins. In the current study, we map the functional interaction between E7 protein and pRB by monitoring the association between a 60-kDa version of the pRB, pRB60, and the cellular transcription factor E2F. We observe that CRII of E7 (amino acids 20 to 29), which completely blocks binding of full-length E7 protein, is necessary but not sufficient to inhibit E2F/pRB60 complex formation. While CRI of E1A (amino acids 37 to 55) appears to be sufficient to compete with E2F for binding to pRB60, the equivalent region of E7 is neither necessary nor sufficient. Only E7 fragments that contained both CRII and at least a portion of the zinc-binding domain (amino acids 60 to 98) inhibited E2F/pRB60 complex formation. These results suggest that pRB60 associates with E7 and E2F through overlapping but distinct domains.

Amino Acid Sequence↗
PubMed1993

Effect of acute resistance exercise on postexercise energy expenditure and resting metabolic rate.

Two separate experiments were performed to determine the effect of acute resistive exercise on postexercise energy expenditure in male subjects previously trained in resistive exercise. In experiment 1, after measurement of their resting metabolic rate (RMR) at 0700 h and their ingestion of a standardized meal at 0800 h, seven subjects (age range 22-40 yr) beginning at 1400 h completed a 90-min weight-lifting protocol. Postexercise metabolic rate (PEMR) was measured continuously for 2 h after exercise and compared with a preexercise baseline. RMR was measured the following morning 15 h after completion of the workout. In experiment 2, six different men (age range 20-35 yr) completed a similar experimental protocol as well as a control condition on a separate day in which metabolic rate was measured for 2 h after a period of quiet sitting. For both experiments, PEMR remained elevated for the entire 2-h measured recovery period, with the average oxygen consumption for the last 6 min elevated by 11-12%. RMR measured the morning after exercise was 9.4% higher in experiment 1 and 4.7% higher in experiment 2 than on the previous day. In experiment 2, the postabsorptive respiratory exchange ratio was significantly lower the morning after the exercise bout. Strenuous resistive exercise may elevate PEMR for a prolonged period and may enhance postexercise lipid oxidation.

Adult↗
PubMed1993

PEIRS: a pathologist-maintained expert system for the interpretation of chemical pathology reports.

Provision of a comprehensive interpretative service is an important challenge facing chemical pathologists. Attempts to automate report interpretation using expert systems have been limited in the past by the difficulties of rule base maintenance. We have applied a novel knowledge acquisition technique, ripple down rules, in the development of PEIRS (Pathology Expert Interpretative Reporting System), a user-maintained expert system for automating chemical pathology report interpretation. We created over 950 rules for thyroid function tests, arterial blood gases and other test sub-groups in 9 mths of operation. A staff pathologist performed all maintenance tasks as part of his routine duties without any need for computer programming skills. No clerical staff involvement was required. Duplication of rule addition for reports requiring multiple comments was the only limitation to coverage of other high volume test groups. PEIRS is the first expert system for the automated interpretation of a range of chemical pathology reports which operates in routine use without extra staffing requirements. PEIRS does not require "knowledge engineering" expertise. Thus, the knowledge base is flexible and can be easily maintained and updated by the pathologist. Expert systems based on ripple down rules should enable pathologists to provide a comprehensive automated interpretative service within the context of the total testing process.

Chemistry, Clinical↗
PubMed1993

Metabolism of caffeine and theophylline in rats with malaria and endotoxin-induced fever.

1. The effects of malaria infection due to Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of orally-administered caffeine (CA: 10 mg/kg) to its primary metabolites (theobromine (TB), paraxanthine (PX) and theophylline (TH)) were studied in 5-week-old male Wistar rats (n = 5 for each treatment). In separate experiments, the effects of malaria and endotoxin-induced fever on the clearance of i.v.-administered theophylline (TH; 15 mg/kg) were studied in another group of rats. 2. The ratios of CA to the three primary metabolites (TB/CA, PX/CA, PH/CA) determined in a single plasma sample obtained 3 h after CA administration were significantly reduced (p < 0.05) both by malaria and fever compared with control (saline) treatment. The clearance of TH determined from the concentration of TH in a single plasma sample obtained 6 h after TH administration was significantly reduced (p < 0.05) by fever but not malaria (4.0 +/- 0.7 ml/min/kg in controls; 4.2 +/- 0.5 in malaria; 2.4 +/- 0.4 in fever). 3. These results suggest that malaria and fever have different effects on CA and TH metabolism in vivo, probably as a result of different effects on the hepatic isozymes involved.

Administration, Oral↗
PubMed1992

Selective determination, in plasma, of artemether and its major metabolite, dihydroartemisinin, by high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of artemether and its major metabolite dihydroartemisinin in plasma has been developed. It involves extraction of plasma with dichloromethane, solid-phase separation of the two analytes and acid decomposition prior to chromatography on a C18 Spherisorb column with a mobile phase of acetonitrile-water (50:50, v/v). Run time is 30 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies.

Artemether↗
PubMed1992

The effect of malaria infection on 3'-azido-3'-deoxythymidine and paracetamol glucuronidation in rat liver microsomes.

The effect of malaria infection on UDP-glucuronosyltransferase (UDPGT) activity was investigated in rat liver microsomes using 3'-azido-3'-deoxythymidine and paracetamol. The Michaelis-Menten parameters, Km and Vmax were calculated and intrinsic clearance values were estimated for normal and infected livers. The results show that malaria infection alters the activity of UDPGT.

Acetaminophen↗
PubMed1992

Recent progress in potassium channel opener pharmacology.

Potassium (K) channel openers comprise a diverse group of molecules capable of opening K channels in excitable cells. These agents exhibit their greatest potency in the smooth muscle system but K channels in cardiac muscle, neurones and in secretory cells are also affected. The development of tissue selectivity is currently one major focus of research and evidence is starting to emerge that this can be achieved. The profound effects of the K channel openers in vivo has led to the suggestion that an endogenous K channel opener might exist and exert an important role in blood pressure homeostasis. The discovery of such a substance--endothelium-derived hyperpolarizing factor--has many implications and its role in cardiovascular regulation is currently under investigation. In vivo, initial studies with the K channel openers emphasized their antihypertensive properties. However, later studies have concentrated on the improvement to coronary blood flow produced by these substances together with their protective effect on the ischaemic myocardium, the basis of which is not fully understood. In spite of great efforts, the K channel which forms the target of these agents in smooth muscle is a matter of controversy. The ability of glibenclamide to antagonize the actions of the K channel openers initially led to the suggestion that an ATP-dependent K channel was their site of action in smooth muscle although the most recent data have implicated a smaller conductance K channel.

Animals↗
PubMed1992

Cocaine in perspective.

In a medical text published in 1883, Dr Benjamin Ward Richardson FRS denounced the evils of tea drinking, suggesting that it commonly gave rise to an 'Extremely nervous semi-hysterical condition'. That this distinguished Victorian physician could take such a view invites a sensitivity toward the perspective within which any debate on drugs is conducted--the historical, cultural and professional assumptions which will colour views as to what needs to be explained and how explanation is to be accomplished. The reality and significance of 'perspective' is further illustrated by examples drawn from contemporary literature which contrast the laboratory and social science approaches to study of cocaine. No one narrow disciplinary perspective on the cocaine problem will suffice; the challenge is to build bridges.

Animals↗
PubMed1992

Role of immersion refractometry for investigating laser-induced effects in cells.

The broad background of scattered light observed in spectra of cell suspensions is reduced by factors of up to 20 by immersion refractometry allowing for improved spectroscopic determination of the absorption properties of cells in the 325-820 nm range. Refractive-index matched spectra of E. coli C1a exhibit a set of resonant features near 422, 561, and 582 nm. Exposure wavelengths are chosen based on this spectrum and cell viability is investigated in E. coli suspensions exposed to 350, 400, 422, 440, and 700 nm radiation delivered in nanosecond pulses with total doses from 500 millijoules to 60 Joules. We observe a loss in cell viability for doses greater than 1 Joule at 422 nm and for all doses at other wavelengths; exposures of less than 1 Joule at 422 nm enhance growth. Excluding exposures at wavelengths within the resonant feature, longer wavelengths are less effective at reducing the viability of E. coli C1a. This indicates the occurrence of at least two absorption processes.

Absorption↗
PubMed1992

Hearing the noise in the system. Exploration of textural analysis as a method for studying change in drinking behaviour.

This paper explores how treatment research is to catch within its design those many unplanned influences which lie outside therapeutic control, but which may influence processes of change. These factors are excluded from the conventional controlled trial. The background literature is briefly reviewed. A study is then described which employed a computer assisted method of textual analysis and an entirely open-ended coding system. The material which was analysed derived from interviews with 49 subjects whose accounts were tape recorded 10 years after treatment contact. Episodes of successful or unsuccessful 'change attempt' (CA) were identified. The two types of CA were compared in relation to coded issues pertaining to the periods before, during and after the episode. A number of significant findings are reported. In the pre-attempt phase 'Success' CAs were significantly associated with traumatic events in the person's life, and with a variety of positive and negative events. During the 'attempt' phase, 'Success' was associated with choice of an abstinence goal. For 'post-attempt', 'Success' was associated with 'Substitution', 'Altruism', 'Fulfillment', and finding the process 'Difficult'. The very preliminary nature of these findings is stressed and the need for further rigorous methodological development.

Adult↗
PubMed1992

Engaging patients with alcohol problems in treatment: the first consultation.

This paper considers the impact of the first consultation at a specialist alcohol clinic on patients' perceptions of their drink problem and on their expectations of help from three sources: an alcohol clinic, general practitioners and Alcoholics Anonymous. At intake, males had higher expectations than females of help from the alcohol clinic while people in manual occupations and those in the 'less heavy' drinking category had higher expectations of general practitioner help than other patients. Change was found to occur during the first clinic consultation so that by the end of the session patients had raised their rating of problem severity and their expectations of help from the three sources examined. Overall, patient perceptions of the clinic assessment session were positive. The study highlights the importance of obtaining a full understanding of the process of engagement in treatment and indicates the potential of a clinical assessment to effect change in patient attitudes.

Adult↗
PubMed1992

The use of services for alcohol problems: general practitioner and specialist alcohol clinic.

A sample of 40 patients referred to a specialist alcohol clinic were given a full assessment by a clinician and then randomly allocated to one of two groups. The first group received continuing care from the clinic. The second group were returned to the management of their general practitioners who were offered specialist support in caring for their patients. Patients and general practitioners were followed-up 6 months after the clinic assessment. This paper reports on the uptake of clinic and general practice services by patients and examines the possible factors associated with continuing attendance, including patient attributes, service activity, patients' self-assessments of their drink problem and their expectations of help from services. Qualitative data is used to examine patients' perceptions and experiences of clinic and general practice-based care for drinking problems. The findings highlight some of the difficulties reported by patients in receiving help for their problems particularly from general practitioners.

Adult↗
PubMed1992

Inhibition by adrenergic neurone blocking agents of the relaxation induced by BRL 38227 in vascular, intestinal and uterine smooth muscle.

1. The adrenergic neurone blocking agents, guanethidine and bretylium, have been tested for inhibitory activity against the actions of some relaxant drugs (BRL 38227, noradrenaline, sodium nitroprusside, theophylline) in vascular, intestinal and uterine smooth muscle. 2. In guinea-pig isolated taenia caeci pre-contracted with KCl (25 mM), BRL 38227 (0.1-10 microM) and noradrenaline (10 nM-100 microM) each caused concentration-dependent relaxation. Guanethidine and bretylium (50 microM) each antagonized the relaxation to BRL 38227 but not that to noradrenaline. At high concentration (500 microM), the adrenergic neurone blocking agents antagonized the action of BRL 38227 and, to some extent, that of noradrenaline. 3. In rat isolated aorta pre-contracted with noradrenaline (300 nM), BRL 38227 (0.0125-3.2 microM) and sodium nitroprusside (0.3-100 nM) each produced concentration-dependent smooth muscle relaxation. Guanethidine and bretylium (5-500 microM) each antagonized the action of BRL 38227 without antagonizing that of sodium nitroprusside. 4. Rats were pretreated with 17-beta oestradiol benzoate. Tension waves were then induced from segments of isolated, oestrogen-dominated uterus by transmural electrical stimulation or by oxytocin (0.2 nM). These tension waves were inhibited by BRL 38227 (0.025-3.2 microM) or theophylline (0.05-0.8 mM) in a concentration-dependent manner. Guanethidine (50 microM) antagonized the action of BRL 38227 in both the electrically- and oxytocin-driven tissues. In the electrically-driven tissues, guanethidine (50 microM) did not antagonize the inhibition to theophylline. 5. In KCl (25 mM)-treated guinea-pig taenia caeci, guanethidine (50 microM) inhibited the efflux of 86Rb+ evoked by BRL 38227 (10 microM) but not that evoked by noradrenaline (10 microM). In contrast, apamin(100 nM) reduced the efflux of 86Rb+ which was promoted by noradrenaline, but did not affect efflux induced by BRL 38227.6. It is concluded that the adrenergic neurone blocking agents, guanethidine and bretylium (each at 50 microM), selectively inhibit the relaxant action of BRL 38227 in vascular, intestinal and uterine smooth muscle. If this inhibition reflects direct blockade of the K+-channel (KKCO) which is opened by BRL 38227, then the adrenergic neurone blocking agents act as inhibitors selective for KKCO as opposed to the small, apamin-sensitive (SKCa) and large (BKca) conductance, Ca2"-dependent K+-channels.

Animals↗
PubMed1992

Potassium channel modulation in rat portal vein by ATP depletion: a comparison with the effects of levcromakalim (BRL 38227).

1. The effects of levcromakalim and of adenosine 5'-triphosphate (ATP) depletion on membrane potential and ionic currents were studied in freshly-dispersed smooth muscle cells of rat portal vein by use of combined voltage- and current-clamp techniques. 2. Levcromakalim (1 microM) induced a glibenclamide-sensitive, non-inactivating K-current (IKCO) and simultaneously inhibited the slow, transient outward, delayed rectifier K-current (ITO). Levcromakalim also hyperpolarized the portal vein cells by approximately 20 mV. 3. Reduction of intracellular ATP by removal of glucose and carboxylic acids from the recording pipette and of glucose from the bath fluid, induced a slowly-developing, non-inactivating and glibenclamide-sensitive K-current (Imet) within 60-300 s after breaking the membrane patch. Imet reached peak amplitude after 300-900 s, remained at a plateau for 200-800 s and then slowly ran down. At the peak of Imet, the cells were hyperpolarized by approximately 20 mV and their input conductance was increased by 42%. 4. At the time of maximum development of Imet, the delayed rectifier current, ITO, was reduced by 48%. 5. In the absence of glucose and carboxylic acids, addition of 1 microM free ATP to the recording pipette almost doubled the magnitude of Imet. At a holding potential of -10 mV, Imet was increased from 124 +/- 11 pA to 228 +/- 54 pA whereas the time-course of development and run-down of Imet was unaffected. 6. During the development and after the run-down of Imet, levcromakalim (1-10 microM) failed to induce IKCO. 7. Stationary fluctuation analysis of the current noise associated with Imet revealed a unitary conductance of between 10-20 pS in a physiological potassium gradient. A second contaminating current with an underlying unitary conductance of approximately 150 pS remained after Imet had run down. 8. It is concluded that IKCO induced by levcromakalim and Imet are carried by the same population of relatively small conductance, glibenclamide-sensitive K-channels. The open state of these is increased by procedures designed to lower intracellular ATP concentrations. 9. The simultaneous inhibition of the delayed rectifier current (ITO) by both levcromakalim and during the development of Imet is highly significant. It suggests that levcromakalim could modify the interaction of ATP with sites linked to more than one type of K-channel. This results in the opening of those channels which underlie IKCO (and which are normally inhibited by ATP binding) together with the modulation of phosphorylation-dependent channels such as those which underlie ITO.

Adenosine Triphosphate↗
PubMed1992

The involvement of potassium channels in the action of ciclazindol in rat portal vein.

1. In whole portal veins, ciclazindol (0.3-10 microM) increased the amplitude and duration, but decreased the frequency of spontaneous contractions. Glibenclamide (0.3-10 microM) produced a small increase in contraction amplitude and duration with a small reduction in contraction frequency. 2. In whole portal veins, ciclazindol (1-10 microM) antagonized the relaxant effects of BRL 38227 in a non-competitive manner. Under identical conditions, the effects of glibenclamide (0.3-10 microM) appeared to be competitive. 3. In whole portal veins loaded with 42K, ciclazindol itself (up to 3 microM) had no detectable effect on basal 42K exchange. However, the increase in 42K efflux produced by BRL 38227 (5 microM) was antagonized by ciclazindol (3 microM). Similar effects were produced by glibenclamide (up to 3 microM). 4. In freshly-isolated portal vein cells examined by the whole-cell voltage-clamp technique, ciclazindol (1-100 microM) inhibited the slowly-activating and inactivating transient outward current (ITO) which could be generated at potentials more positive than -30 mV. In addition ciclazindol (1-10 microM) inhibited the non-inactivating K-current (IKCO) induced by BRL 38227 (10 microM). 5. In freshly-isolated portal vein cells under current-clamp conditions, the hyperpolarization produced by BRL 38227 (10 microM) was reversed by ciclazindol (1-10 microM). 6. In porcine brain membrane fragments, glibenclamide (0.65 nM) displaced 50% of the binding of [3H]-glibenclamide whereas ciclazindol (up to 10 microM) had no effect. 7. It is concluded that ciclazindol is a K-channel blocker. Its action is not selective for the channel(s) which carry IKCO but also extends to those which carry ITO.Its inability to displace [3H]-glibenclamide from porcine brain fragments may indicate that antagonism of BRL 38227 by ciclazindol in smooth muscle is exerted at a site different from that of glibenclamide.

Animals↗