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Biomedical subjects

D Harper

Publications and source records attributed to D Harper.

At least 19 recordsLinked to original sources
PubMed1992

Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5-HT2 receptor.

1. The 5-HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation. 2. Fenoldopam was an agonist at the vascular 5-HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5-hydroxytryptamine (5-HT). Fenoldopam had an affinity (pKA) of 5.84 +/- 0.04 and efficacy (tau) of 0.57 +/- 0.04, whereas 5-HT had a pKA of 6.65 +/- 0.12 and tau of 2.66 +/- 0.41. 3. The constrictor effects of fenoldopam and 5-HT were competitively antagonized by the 5-HT2 antagonist, ketanserin, with pKB values of 8.81 +/- 0.11 and 8.83 +/- 0.10 respectively. 4. Prior incubation with fenoldopam produced a concentration-related rightward shift of a subsequent 5-HT concentration-response curve. This inhibition was specific for 5-HT since constrictor responses to angiotensin II were unaffected. 5. This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5-HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5-HT.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

e-PTFE ventricular shunt catheters.

The perfect polymer surface for implantation should resist the adhesion of bacteria while producing no reaction in surrounding tissues. Silicone elastomer is a common material used for medical implantation devices. This material is superior to most available for implantation because of its flexibility and low, but detectable, tissue reaction. We have evaluated a flexible, expanded polytetrafluoroethylene (e-PTFE) ventricular catheter for cerebrospinal fluid shunting and have found that although e-PTFE is safe for cerebral implantation, the porosity of the material allows tissue ingrowth that obstructs the lumen. Our limited clinical evaluation of 5-microns internodal distance e-PTFE revealed that this open-cell structure, allowing tissue ingrowth, apparently is a poor candidate to replace silicone elastomer in cerebrospinal fluid shunting devices. However, further investigation may provide a polymer superior to silicone elastomer to create a cerebrospinal fluid shunt.

Animals↗
PubMed1991

An outbreak of Legionnaires' disease in Gloucester.

Fourteen people living in or near the city of Gloucester fell ill with Legionnaires' disease caused by Legionella pneumophila serogroup (SG) 1 between 27 August and 27 October 1986. Another patient had fallen ill on 30 May. Nine of the 15 were diagnosed retrospectively during a case finding exercise. There were three deaths. Three cases of Pontiac fever were also diagnosed. The source was probably one or more wet cooling towers. Nineteen premises in the city with such towers were identified, and three just outside Gluocester. Samples from 11 of the 22 premises grew Legionella spp.; from nine of these L. pneumophila SG 1 (Pontiac) was isolated. The efficacy of regular addition of biocide in addition to hypochlorite added at the time of disinfection in inhibiting the growth of Legionella spp. was demonstrated. A survey of patients' movements during their likely incubation period showed that there was no single building that all patients had visited, but there were two areas of the city which nearly all had visited or passed through by car. A case-control study demonstrated an association with one of these areas. Cooling towers near both areas may have been sources but the evidence is insufficient to incriminate any single one. The unexpected finding of L. pneumophila SG 1 (Pontiac) in nine towers supports the hypothesis that there may have been multiple sources. Cooling towers may have been contaminated by mains water or by drift from other towers.

Adult↗
PubMed1991

Estimation of the efficacy and affinity of the beta 2-adrenoceptor agonist salmeterol in guinea-pig trachea.

1. We have attempted to estimate the affinity and efficacy of the new beta 2-adrenoceptor agonist salmeterol in the guinea-pig isolated trachea and to compare these estimates with those obtained for salbutamol. 2. The kinetics of the relaxation to salmeterol were considerably slower than those to salbutamol and the responses were poorly defined. Nevertheless, in experiments employing a cumulative curve design both salmeterol and salbutamol exhibited partial agonist behaviour. Operational model-fitting of these data indicated that the intrinsic efficacies of the two agonists were indistinguishable but that salmeterol had an affinity (pKA = 7.4) some 30 fold greater than salbutamol (pKA = 5.9). 3. Single dose experiments, using maximally effective concentrations of salmeterol or salbutamol were carried out in an attempt to quantify more reliably the relative efficacies of the two agonists. In these experiments salbutamol was found to have an efficacy (2.5) approximately 3 fold greater than that of salmeterol (0.8). 4. Full/partial agonist interaction studies were carried out to provide another estimate of the affinity of salmeterol. Isoprenaline and adrenaline were employed as full agonists in these experiments and the affinity (pKB) estimates obtained for salmeterol against these agonists were 7.3 and 7.4 respectively. These affinity estimates were similar to the pKA value (7.4) obtained by operational model-fitting. 5. Salmeterol has slightly lower efficacy (3 fold) but markedly greater affinity (30 fold) than salbutamol at beta 2-receptors. The slightly lower efficacy of salmeterol is unlikely to have clinical implications for this drug as a bronchodilator beta 2-adrenoceptor agonist in asthma.

Adrenergic beta-Agonists↗
PubMed1990

The Stafford outbreak of Legionnaires' disease.

A large outbreak of Legionnaires' disease was associated with Stafford District General Hospital. A total of 68 confirmed cases was treated in hospital and 22 of these patients died. A further 35 patients, 14 of whom were treated at home, were suspected cases of Legionnaires' disease. All these patients had visited the hospital during April 1985. Epidemiological investigations demonstrated that there had been a high risk of acquiring the disease in the out patient department (OPD), but no risk in other parts of the hospital. The epidemic strain of Legionella pneumophila, serogroup 1, subgroup Pontiac 1a was isolated from the cooling water system of one of the air conditioning plants. This plant served several departments of the hospital including the OPD. The water in the cooling tower and a chiller unit which cooled the air entering the OPD were contaminated with legionellae. Bacteriological and engineering investigations showed how the chiller unit could have been contaminated and how an aerosol containing legionellae could have been generated in the U-trap below the chiller unit. These results, together with the epidemiological evidence, suggest that the chiller unit was most likely to have been the major source of the outbreak. Nearly one third of hospital staff had legionella antibodies. These staff were likely to have worked in areas of the hospital ventilated by the contaminated air conditioning plant, but not necessarily the OPD. There was evidence that a small proportion of these staff had a mild legionellosis and that these 'influenza-like' illnesses had been spread over a 5-month period. A possible explanation of this finding is that small amounts of aerosol from cooling tower sources could have entered the air-intake and been distributed throughout the areas of the hospital served by this ventilation system. Legionellae, subsequently found to be of the epidemic strain, had been found in the cooling tower pond in November 1984 and thus it is possible that staff were exposed to low doses of contaminated aerosol over several months. Control measures are described, but it was later apparent that the outbreak had ended before these interventions were introduced. The investigations revealed faults in the design of the ventilation system.

Adult↗
PubMed1990

Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms.

1. Recent theoretical studies have questioned the pharmacological estimation of agonist affinity. They showed that when receptor isomerisation or ternary complex mechanisms operate, the receptor inactivation method can substantially overestimate affinity, whereas methods for partial agonist analysis are more accurate. We previously suggested that the operation of such mechanisms and therefore the presence of errors could be detected by analysing the same partial agonist by the receptor inactivation and comparative methods. This paper describes the practical application of this test. 2. The ternary complex mechanism was simulated for a partial agonist under various conditions relating receptor (R) and transducer (T) concentrations, one of which also corresponds to the receptor isomerisation mechanism. The theoretical data so generated were then analysed by the inactivation and comparative methods to quantify the magnitude of error of affinity estimation that could occur. 3. This analysis showed that for a partial agonist with approximately 85% of the activity of a full agonist, the inactivation method could produce an affinity (pKA) estimate up to 0.7 log10 units higher than that produced by the comparative method. This difference would occur when the total receptor concentration ([R0]) is less than or equal to the total transducer concentration ([T0]). It also showed that the overestimation of affinity by the inactivation method was accompanied by drastic overestimation of Em, the maximal effect parameter. 4. The test was then exemplified using the muscarinic receptor system in the guinea-pig isolated left atrial preparation, where there is evidence that a ternary complex mechanism operates. The test agonist was pilocarpine, which produced on average 83% of the activity of the full agonist, carbachol. Pilocarpine was analysed in comparison with carbachol and by receptor inactivation in the same tissue resulting in small and statistically insignificant differences in Em (96.7% and 97.3% respectively) and pKA (5.03 and 4.95 respectively). 5. In conclusion, in this experimental system, there was no evidence for the errors in agonist affinity estimation predicted by theory. Although this conclusion only applies to this system and application of the test to others is necessary to establish the generality of the present results, further examination of the theoretical basis for the predicted errors is required.

Animals↗
PubMed1989

Do pharmacological methods for the quantification of agonists work when the ternary complex mechanism operates?

It is well established that many receptors couple to G-proteins in order to subserve their pharmacological or physiological effects. In those systems it is possible that a ternary complex mechanism operates in which initiation of an effect depends on the concentration of agonist-receptor-G-protein complex formed. Such systems may be considered to obey a receptor-transducer model (Black & Leff, 1983, Proc. R. Soc. B220, 141). A theoretical analysis of this model is presented which seeks to determine how the operation of the ternary complex mechanism affects the quantification of agonists by conventional pharmacological methods. Previous analyses have concluded that pharmacological models may or may not accommodate the ternary complex mechanism depending upon the relationship between the relative concentrations of receptor and transducer units, [R0], and [T0] respectively. The present study extends these in two ways. It considers the impact of the ternary complex mechanism on agonist quantification under a more complete range of conditions relating [R0] and [T0], and it does so with regard to the analysis of partial agonists (by the comparative method) as well as of full agonists (by the method of receptor inactivation). The following predictions are made: (i) reliable estimates of affinity and efficacy can be made using the comparative method under the conditions [R0] much greater than [T0] and [R0] much less than [T0] whereas the inactivation method only works under the former condition; (ii) errors occur in the estimation of affinity and efficacy by both methods when [R0] = [T0] although better estimates are produced by the comparative method; (iii) when errors occur in the absolute estimation of affinity and efficacy, the orders of affinity and efficacy determined by the comparative method will generally be correct but this is not the case for the inactivation method; (iv) in general, the comparative method for agonist quantification appears to produce more reliable information for the purposes of receptor classification and medicinal chemistry than does the receptor inactivation method.

Chemical Phenomena↗
PubMed1989

Legionnaires' disease and the sick-building syndrome.

In October 1985, six cases of legionnaires' disease were associated with a police headquarters building. Four were amongst staff who worked in or visited the communications wing of the headquarters and two cases occurred in the local community. A case-control study implicated the operations room of the communications wing as the main area associated with infection. This wing was air-conditioned and smoke tracer studies showed that drift from the exhaust as well as from the base of the cooling tower entered the main air-intake which serviced the air-conditioning system. Legionella pneumophila serogroup 1 subgroup pontiac was isolated from water and sludge in the cooling tower pond. Contaminated drift from the top of the cooling tower was probably responsible for the two community cases. An additional discovery was that symptoms suggestive of the sick-building syndrome were associated with working in this wing.

Adult↗
PubMed1989

Effect of posture on the plasma levels of atrial natriuretic factor.

Atrial natriuretic factor (ANF) is a peptide with potent natriuretic, diuretic and vasorelaxant activities. Stretching of the right atria causes release of ANF into the circulation. Therefore, changes in central blood volume or acute volume expansion are likely to change the plasma levels of ANF. In this study we investigated the effects of changes in posture on the plasma levels of ANF, plasma renin activity (PRA) and plasma aldosterone (aldo). Eight male and five female volunteers ranging in age from 23 to 26 years were placed on a normal sodium intake and on the experimental day blood was obtained for ANF, PRA, and aldo after 30 minutes of lying supine, 30 minutes of 10 or 20 degrees head-down tilt, and 30 minutes of standing. Plasma ANF increased significantly after 30 minutes of head-down tilt from the supine value of 33.7 +/- 5.2 pg/ml to 47.7 +/- 7.7 pg/ml (p less than 0.02) and suppressed to 14.1 +/- 0.02) after 30 minutes of standing. PRA did not change significantly with head-down tilt, (supine 1.64 +/- 0.44 ngAI/ml/h vs. 30 minutes tilt 1.28 +/- 0.32 ngAI/ml/h (p = NS). Plasma aldosterone decreased by head-down tilt from 11.2 +/- 1.2 ng/ml to 8.4 +/- 0.8 ng/dl (p less than 0.02) and returned to the supine level after standing. In conclusion ANF levels change significantly with posture. Increase in central blood volume by head-down tilt increases ANF levels and suppresses plasma aldosterone with no effect on PRA. Standing decreases ANF significantly. These results suggest that for proper interpretation of plasma levels of ANF, posture at the time of sampling has to be standardized.

Adult↗
PubMed1986

An outbreak of gastroenteritis on a passenger cruise ship.

In an outbreak of gastroenteritis on board a cruise ship 251 passengers and 51 crew were affected and consulted the ship's surgeon during a 14-day period. There was a significant association between consumption of cabin tap water and reported illness in passengers. Enterotoxigenic Escherichia coli were isolated from passengers and crew and coliforms were found in the main water storage tank. Contamination of inadequately chlorinated water by sewage was the most likely source of infection. A low level of reported illness and late recognition of the outbreak delayed investigation of what was probably the latest in a series of outbreaks of gastrointestinal illness on board this ship. There is a need for a national surveillance programme which would monitor the extent of illness on board passenger cruise ships as well as a standard approach to the action taken when levels of reported illness rise above a defined level.

Disease Outbreaks↗