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Biomedical subjects

M J Davey

Publications and source records attributed to M J Davey.

At least 19 recordsLinked to original sources
PubMed2001

Accuracy of emergency department bedside ultrasonography.

OBJECTIVES: To determine which focused ultrasound examinations can be interpreted accurately by emergency physicians who have limited training and experience. To determine whether image quality and/or the operator's level of confidence in the findings correlates with accurate scan interpretation. METHODS: A prospective sample of consenting adult emergency department patients with the conditions was selected for study. Scans were performed by emergency physicians who had attended a 3-day focused ultrasound examinations instruction course. All scans were videotaped and subsequently reviewed by a radiologist. Accuracy was determined by comparing the emergency physicians scan interpretation with preselected gold standards. Chi-squared tests were employed to determine if the individual performing the scan, the type of scan, patient's body habitus, image quality and/or operator confidence were reliable predictors of accuracy. RESULTS: Between September 1997 and January 1999, 221 scans were studied. Accuracy varied widely depending on the type of scan performed: aortic scans were 100% accurate whereas renal scans had 68% accuracy. On bivariate analyses, there was little variation in the various operators' levels of proficiency and accuracy of interpretation was not associated with patient body habitus, image quality or operator confidence. CONCLUSIONS: Neophytes can accurately perform and interpret aortic scans; additional training and/or experience appear to be necessary to achieve proficiency in conducting most of the other scans studied. Inexperienced operators are unable to discern whether their scan interpretations will prove accurate.

Adult↗
PubMed2000

Mechanisms of DNA replication.

Advances in recent years have led to exciting new ideas about the initiation, regulation and coordination of DNA replication. Structural studies have yielded fascinating glimpses of replisome action. In addition, the involvement of replication proteins in other cellular processes has blurred the lines between replication, repair and recombination.

DNA Replication↗
PubMed2000

Emergency department ultrasound scanning for abdominal aortic aneurysm: accessible, accurate, and advantageous.

STUDY OBJECTIVE: This study was conducted to determine whether emergency physicians with relatively limited training and experience can accurately identify the presence or absence of abdominal aortic aneurysms (AAAs) by performing bedside ultrasound scanning, and to assess the potential impact of ultrasound scanning on clinical management. METHODS: Patients in whom AAAs were suspected, including those patients older than 50 years presenting with abdominal/back pain of unclear origin or presumed renal colic, were eligible for study entry. Consenting adults had ultrasound scanning by an emergency physician who was not responsible for their primary care. Treating physicians remained blinded to the results unless an unexpected AAAs was discovered. Scan accuracy was ascertained by comparing our ultrasound results with preselected gold standards. The clinical impact of the ultrasound studies was determined by comparing the preultrasound and postultrasound assessment sheets that detailed the presumed diagnosis, proposed investigations and therapies, and patient disposition. RESULTS: Our convenience sample includes 68 scans for AAAs; findings of 26 scans were positive, 40 scans yielded negative findings, and 2 scans were indeterminate. Scan interpretations were 100% accurate. The ultrasound results would have improved the care of 46 patients without adverse sequelae. Ultrasound scanning served primarily to exclude AAA in patients who proved not to have aneurysms; however, scans also provided significant benefits for those with AAAs and improved patient management plans. CONCLUSION: Relative neophytes can perform aortic ultrasound scans accurately. These scans appear useful as a screening measure in high-risk emergency department patients; they may also aid in rapidly verifying the diagnosis in patients who require immediate surgical intervention.

Abdominal Pain↗
PubMed1999

Replisome assembly at oriC, the replication origin of E. coli, reveals an explanation for initiation sites outside an origin.

This study outlines the events downstream of origin unwinding by DnaA, leading to assembly of two replication forks at the E. coli origin, oriC. We show that two hexamers of DnaB assemble onto the opposing strands of the resulting bubble, expanding it further, yet helicase action is not required. Primase cannot act until the helicases move 65 nucleotides or more. Once primers are formed, two molecules of the large DNA polymerase III holoenzyme machinery assemble into the bubble, forming two replication forks. Primer locations are heterogeneous; some are even outside oriC. This observation generalizes to many systems, prokaryotic and eukaryotic. Heterogeneous initiation sites are likely explained by primase functioning with a moving helicase target.

Bacterial Proteins↗
PubMed1997

Modulation of the P1 plasmid partition protein ParA by ATP, ADP, and P1 ParB.

ParA is an essential P1 plasmid partition protein. It represses transcription of the par genes (parA and parB) and is also required for a second, as yet undefined step in partition. ParA is a ParB-stimulated ATPase that binds to a specific DNA site in the par promoter region. ATP binding and hydrolysis by ParA affect ParA activities in vitro. ATP and ADP binding stimulate ParA DNA binding and dimerization; however, ATP hydrolysis has a negative effect on DNA binding. Our current experiments reveal that ATP binding and hydrolysis affect ParA conformation and ParA sensitivity to ParB. Nucleotide binding assays show that ParA binds ATP better than ADP (Kd values of 33 and 50 microM, respectively). Interaction with these nucleotides as well as ATP hydrolysis by ParA alter ParA conformation as established by CD and ParA sensitivity to heat denaturation. Finally, we show that ParB stimulates ParA DNA binding. This stimulation requires ATP hydrolysis in vitro, suggesting that one role for ATP hydrolysis in vivo is to make ParA repressor sensitive to ParB. Our observations lead to the suggestion that ATP binding and hydrolysis have separable roles in ParA repressor function and perhaps in ParA partition functions as well.

Adenosine Diphosphate↗
PubMed1994

The P1 plasmid partition protein ParA. A role for ATP in site-specific DNA binding.

ParA, a P1 protein required for partition of the prophage plasmid, regulates expression of its own gene and another partition gene, parB, from a promoter upstream of parA. The ATP-dependent ParA DNA binding activity to the par promoter is thought to mediate this regulation. An alternate purification for ParA is presented. This highly purified ParA was used to examine ParA DNA binding activity using DNase I protection assays. At high concentration, ParA bound to the par promoter in the absence of ATP, demonstrating that although ATP stimulates, it is not required for DNA binding. Non-hydrolyzable ATP analogues as well as ADP stimulated binding more than ATP, suggesting that the act of hydrolysis is coupled to release of the DNA. Glycerol gradient sedimentation and chemical cross-linking experiments suggest that ParA exists in an monomer-dimer equilibrium that is shifted toward dimer formation by adding ATP or ADP. These observations lead to the proposal that the more active DNA binding form of ParA is a dimer and that the effects of ATP and ParA concentration on DNA binding are a direct result of their effects on oligomerization.

Adenosine Diphosphate↗
PubMed1993

Environmental enrichment following brain damage: an aid to recovery or compensation?

Postoperative environmental enrichment (EC) in rats with brain lesions has been hailed as a potential agent of recovery of function following brain damage. However, most such claims are based on examining the effects of EC on acquisition of a new task following brain injury. Elsewhere we have argued that since this paradigm fails to establish a preoperative behavioural baseline against which to compare subsequent performance it may demonstrate compensation but cannot provide evidence of recovery. The present study directly addresses this issue by examining the effects of postoperative EC both on performance of a preoperatively acquired water maze escape response as well as on de novo acquisition of such a response in rats with bilateral occipital and sham lesions. In terms of swim times postoperative EC was found to significantly improve the performance of subjects which had not been preoperatively trained but not the performance of those subjects which had. However, in terms of a trials to criterion measure postoperative EC benefitted animals in both the preoperative and postoperative training conditions. The results, therefore, support the view that what has been observed in most previous studies is EC-induced compensation rather than recovery and also help to define the conditions under which this occurs. However, they also argue for further investigation of the hypothesis that postoperative EC may enhance recovery of lesion-impaired performance consistency.

Animals↗
PubMed1993

How does environmental enrichment aid performance following cortical injury in the rat?

Understanding how postoperative environmental brain damage in animals may help in devising treatment regimes for brain injured humans. This study tests Finger's hypothesis that EC increases the animal's ability to switch to alternative cues when brain damage renders the cues normally used in performing the task less salient or unavailable. Following preoperative water maze training to visual cues, rats were given either bilateral occipital lesions or sham operations, housed in either EC or standard conditions and then tested in the water maze in alternating visual and non-visual cue conditions. We found no evidence that postoperative EC helped lesioned rats to switch to non-visual cues when visual cues were unavailable.

Acclimatization↗
PubMed1992

Maternal hypothyroxinemia and brain development: II. Biochemical, metabolic and behavioural correlates.

Using a rat model, we have investigated the influence of maternal hypothyroxinemia throughout pregnancy on brain development in young and adult progeny. Although no consistent change was observed in whole brain total protein concentration, the subcellular distribution of protein was adversely affected. Isolation of glycoprotein from developing brain by concanavalin A-affinity chromatography and subsequent resolution by gel electrophoresis revealed the selective compromise of particular glycoprotein species. Furthermore, both control and experimental progeny expressed unique glycoprotein species which either persisted over the period studied or were transient. Calcineurin, a regulator of neurite elongation, was compromised in young progeny, as were a number of lysosomal enzymes (beta-D-glucosidase and aryl sulphatase). In adult progeny, the content of cerebroside sulphate (a major myelin galactolipid) was reduced in midbrain and paleocortex, and brain region-specific compromise was observed for acetylcholine metabolic enzymes. These changes were associated with alterations in behavioural output. We conclude that the availability of maternal thyroxine to the fetus may be a critical determinant for normal brain development and function.

Animals↗
PubMed1989

Pharmacologic basis for the use of doxazosin in the treatment of essential hypertension.

The drug treatment of mild hypertension has been shown to afford protection against fatal and nonfatal strokes, congestive heart failure, progression to more severe levels of hypertension, and all-cause mortality, but not against the complications of coronary artery disease. The lack of benefit against coronary artery disease may result from failure to reduce other risk factors or because the drugs employed increased coronary risk. It can be taken as axiomatic that effective preventive antihypertensive therapy is more likely with drugs with mechanisms and sites of action that are focused on the underlying pathophysiology than with drugs that lower blood pressure by means unrelated to the hypertensive process. Adrenergic predominance plays a major role in the initiation and maintenance of essential hypertension and, consequently, the alpha-adrenergic receptor inhibitors were among the first substances to receive serious consideration as antihypertensive agents. However, since these drugs are nonselective, feedback control of transmitter norepinephrine was lost and, consequently, the clinical expectations of the early alpha-adrenergic receptor inhibitors in the treatment of high blood pressure were not fulfilled. The discovery of selective postjunctional alpha 1-adrenergic-receptor inhibitors, such as prazosin and doxazosin, which preserve feedback control of transmitter norepinephrine release, was the crucially important step in the development of specific drugs to combat the hyperactivity of adrenergic vasoconstrictor nerves in hypertension. These drugs have been shown to normalize hemodynamics in hypertensive patients. They lower blood pressure through a reduction in peripheral resistance at rest and during exercise, independent of changes in heart rate and blood pressure, with minimal reflex activation or tolerance development. Alpha 1-adrenergic-receptor inhibitors, such as prazosin and doxazosin, represent an attractive choice for initial therapy in all grades of hypertension and are especially appropriate in hypertensive patients with congestive heart failure, asthma and chronic obstructive airways disease, renal impairment, diabetes mellitus, hyperlipidemia, benign prostatic hyperplasia, or gout, and in those involved in vigorous work, sports, or exercise. There are no known contraindications to these drugs, except in patients who are sensitive to quinazolines.

Adrenergic alpha-Antagonists↗
PubMed1989

Autoradiographic analysis of alpha-adrenoceptors and muscarinic cholinergic receptors in the hyperplastic human prostate.

Radioligand receptor binding and autoradiography were used to characterize, localize and compare alpha-1 and alpha-2 adrenoceptors and muscarinic cholinergic receptor populations in human benign prostatic hyperplastic tissue. The binding of selective alpha-1 and alpha-2 ligands, [3H]-prazosin and [3H]-UK 14,304, to homogenates of human central and peripheral prostate was saturable and of high affinity. Scatchard analysis produced an equilibrium dissociation constant (KD) of 0.51 +/- 0.10 nM for alpha-1 adrenoceptors, and 2.34 +/- 0.40 nM for alpha-2 adrenoceptors. The mean densities, Bmax, of alpha-1 and alpha-2 adrenoceptors identified in the human adenomatous prostate were 65.9 +/- 12.9 and 36.1 +/- 7.0 fmoles/mg. protein respectively. Receptor autoradiography was used to examine the distribution of muscarinic cholinergic receptors [( 3H]-QNB), alpha-1 adrenoceptors [( 3H]-prazosin]), and alpha-2 adrenoceptors [( 3H]-rauwolscine) on consecutive sections of benign hyperplastic prostatic tissue. Although both subtypes of adrenoceptor were seen in the stromal component of the hyperplastic prostate, there was a substantial predominance of alpha-1 adrenoceptors. A densitometric computer-assisted analysis was performed on the autoradiographic slides to determine the mean ratio of specific alpha-1: alpha-2 adrenoceptors in the stromal compartment of the hyperplastic tissue. The ratio, expressed as % grain occupancy/unit area, was 3.9 +/- 0.75, which is in agreement with a functional alpha-1 adrenoceptor predominance shown in previous studies. Although sparsely distributed in the stroma, a dense alpha-2 adrenoceptor population was seen in association with blood vessels, and in close proximity to the base of some of the [3H]-QNB-labelled prostatic glandular epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Characterisation of human prostatic adrenoceptors using pharmacology receptor binding and localisation.

Benign prostatic enlargement is a common cause of bladder outlet obstruction. Recent work has demonstrated the important role played by the sympathetic nervous system in the control of prostatic muscle tone. Although isometric muscle strip studies and clinical trials have highlighted the influence of alpha-1 adrenoceptors, radioisotope ligand binding studies have demonstrated a relatively increased density of alpha-2 adrenoceptors in the muscle within prostatic tissue, the significance of which is as yet unexplained. Forty patients entered a study using pharmacological muscle strip experiments, radioligand binding assays and receptor autoradiography. Pharmacological data from these studies confirmed that contraction of prostatic muscle is mediated predominantly by alpha-1 adrenoceptor stimulation, with no evidence of significant alpha-2 adrenoceptor or cholinergic mediated effects. Radioligand binding studies confirmed that there is a higher concentration of alpha-1 binding sites as contrasted to alpha-2 within normal prostate, but that this relationship approaches equity in adenomatous prostate. Autoradiographic localisation demonstrated that alpha-1 adrenoceptor binding is predominant within prostatic stroma with only a small component of alpha-2 adrenoceptors in this compartment. This comprehensive study supports the suggestion that prostatic muscular contraction is controlled by the influence of the sympathetic nervous system acting via alpha-1 adrenoceptors. These findings support the therapeutic use of specific alpha-1 adrenoceptor blockade in the management of benign prostatic hyperplasia.

Adult↗
PubMed1988

Environmental enrichment and recovery from a complex Go/No-Go reversal deficit in rats following large unilateral neocortical lesions.

Postoperative environmental enrichment in brain-lesioned rats has been found to enhance performance in tasks in which a range of sensory cues can be utilized but not in tasks in which information from one particular sensory modality is essential to goal attainment. This has generally been construed as evidence of a role for environmental enrichment in facilitating compensation for sensory loss but not recovery of lost function per se. However, most published investigations have adopted an experimental design which fails to empirically separate the processes of recovery and compensation. The present investigation, by employing a unisensory task and using unilateral cortical lesions, thus markedly reducing the functional value of compensatory mechanisms in the mediation of postoperative behaviour, seeks to distinguish the contributions of these processes. The results show a sizeable hemidecorticate deficit on a visual operant Go/No-go reversal task but fail to provide clear evidence of any facilitation of functional recovery as a result of postoperative environmental enrichment.

Animals↗
PubMed1988

Effect of a digital imaging network on physician behavior in an intensive care unit.

This study examined the effect of a medical image management network on the behavior of physicians working in a medial intensive care unit (MICU). For 1 year, 8-week periods during which chest radiographs were digitized and made available to MICU physicians on a digital display console were alternated with 8-week periods during which only film images were available. Clinical efficacy during the periods was compared by measuring the time between completion of imaging examinations and initiation of specific clinical actions such as placement and positioning of tubes. Results indicate that the time required to take some clinical actions decreased with the immediate availability of images on the digital display console. Established procedures for obtaining radiologic information were altered by the digital imaging network. The time at which physicians viewed images changed, and consultations between MICU staff and radiologists decreased. These results indicate that behavior patterns are altered when a new technology replaces an existing one. Optimal use of this technology may require changes in the logistics of clinical practice.

Behavior↗
PubMed1987

Environmental enrichment and recovery from contralateral sensory neglect in rats with large unilateral neocortical lesions.

Previous investigations of the potential value of postoperative environmental enrichment in enhancing functional recovery in brain-lesioned rats have yielded contradictory results. The present study sought to resolve some of the contradictions by drawing a clear distinction between the contribution of environmental enrichment to the processes of compensation for sensory loss and recovery per se. By using unilateral lesions, thus avoiding total loss in any sensory modality, and examining a behavioural deficit not anyway thought to be, primarily, a consequence of sensory loss, it was hoped to arrive at an experimental test in which reinstatement of preoperative performance would necessarily reflect recovery rather than compensation. Recovery from the effects of large unilateral neocortical removals on performance on the 'bracelets' test, recently proposed by Schallert and Whishaw, Behavioural Neuroscience, 1984, 98: 518-540, as a model of simultaneous extinction in humans, was investigated. Lesions significantly impaired bracelet removal from the contralateral paw and a degree of recovery from this impairment was observed. However, recovery was not enhanced by postoperative environmental enrichment. The reasons for this were discussed and possible explanations of the recovery that did occur were considered. Implications for Schallert and Whishaw's model were also discussed. It was concluded that the present results were consistent with the view that any restorative value that postoperative environmental enrichment may have lies in facilitating compensation rather than recovery.

Animals↗
PubMed1987

2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.

Adrenergic alpha-Antagonists↗
PubMed1986

Alpha adrenoceptors--an overview.

The realisation that transmitter noradrenaline modulated its own release through a pre-junctionally located alpha-adrenoceptor operated control mechanism explained several paradoxical phenomena and raised exciting therapeutic possibilities. Characterisation of the pre- and post-junctional effects of agonists and antagonists led to the conclusion that pre- and post-junctional alpha-adrenoceptors differed in receptor structure and alpha-adrenoceptors were sub-divided into alpha 1- and alpha 2-adrenoceptors. It was subsequently shown that in addition to the differences in receptor structure the biochemical mechanisms of signal transduction were entirely different in the case of each sub-type of adrenoceptor. It has been hypothesised that automodulation of transmitter noradrenaline release occurs between neighbouring varicosities in densely innervated organs and as a consequence ensures that homogeneity in tissue noradrenaline concentration is achieved. In the heart the loss of such automodulation could result in inhomogeneity in transmitter concentration and under certain circumstances favour re-entry phenomena and arrhythmogenesis. There is now a large body of evidence documenting the presence of post-junctional alpha 1-adrenoceptors in the mammalian heart. Recent experimental work strongly supports the concept that enhanced alpha 1-adrenoceptor responsiveness plays a primary pathophysiological role in the genesis of malignant dysrhythmias induced by catecholamines during myocardial ischaemia and reperfusion. Alpha 1-adrenoceptor antagonists have been shown to be effective in restoring sinus rhythm after such arrhythmias have been experimentally induced. It is anticipated that alpha 1-adrenoceptor antagonists possessing potent antiarrhythmic activity and causing minimal changes in heart rate and arterial blood pressure, will become available and be employed to ascertain whether or not the animal results translate to man.

Adrenergic alpha-Antagonists↗