Biomedical subjects

A R Davies

Publications and source records attributed to A R Davies.

At least 19 recordsLinked to original sources

PubMed2006

The multidisciplinary team meeting improves staging accuracy and treatment selection for gastro-esophageal cancer.

The object of this article is to assess current staging accuracies for individual modalities and to investigate the influence of the multidisciplinary team (MDT) on clinical staging accuracies and treatment selection for patients with gastro-esophageal cancer. Patients newly diagnosed with gastric or esophageal cancer and who were deemed suitable for surgical resection by the MDT were studied. Patients were staged with a combination of computerized tomography (CT), endoscopic ultrasound (EUS) and laparoscopic ultrasound (LUS). Additionally, the MDT determined an overall clinical stage for each patient after discussion at the MDT meeting. Treatments were selected according to this final clinical stage. Final histopathological staging (pTNM) was available for all patients and was used as the gold standard for determining staging accuracy. Suitability of treatment selection was assessed once final pTNM was available. One hundred and eighteen patients were studied. Endoscopic ultrasound was the most accurate individual staging modality for the loco-regional assessment of esophageal tumors (T stage accuracy 78%, N stage accuracy 70%). Laparoscopic ultrasound was the most accurate modality in T staging of gastric cancers (91%). The MDT stage was more accurate than each individual staging modality for T and N staging for both gastric and esophageal cancers (accuracy range: 88-89%) and was better for the assessment of nodal disease than each individual modality (CT P < 0.001, EUS P < 0.01, LUS P < 0.01). Overall staging accuracy as determined at the MDT meeting was increased and resulted in only 2/118 (2%) patients being under-treated. The MDT significantly improves staging accuracy for gastro-esophageal cancer and ensures that correct management decisions are made for the highest number of individual patients.

Adenocarcinoma↗

PubMed2005

Hypothermia improves outcome from traumatic brain injury.

Hypothermia for patients with severe traumatic brain injury (TBI) remains controversial despite a strong biological rationale and reasonable evidence from the literature. The "negative" Clifton study seems to have reduced enthusiasm for hypothermia, however the aim of this review is to analyse the evidence from all randomised controlled trials (RCT) and meta-analyses on this topic to determine whether there is adequate support for the view that hypothermia does improve outcome from TBI. The biological rationale for hypothermia is supported by animal and human mechanistic studies of TBI and human clinical studies of brain injury caused by out-of-hospital cardiac arrest. Several small single-centre RCT's have demonstrated that hypothermia leads to both improved survival and improved favourable neurological outcome in TBI. The Clifton study, which was larger and multi-centre, found hypothermia had no major benefits in TBI, although this study can be criticised for several issues of trial methodology (trial design and application of the intervention) and group comparison. Several meta-analyses have given slightly discordant results, but the two most recent meta-analyses agree that hypothermia improves favourable neurological outcome and probably survival. Subsequent to these meta-analyses, a RCT was published which has confirmed that hypothermia is beneficial in a large group of TBI patients. When the published evidence is considered in total, even if hypothermia can't be justified in all TBI patients, if it is applied optimally in the most appropriate patients, hypothermia certainly improves outcome from TBI. If hypothermia is correctly applied (early, long and cool enough) in the optimal group of TBI patients (young with elevated ICP), there seems to be no doubt that hypothermia is effective in improving both survival and favourable neurological outcome from TBI.

Journal Article↗

PubMed2003

Impact of increasing parenteral protein loads on amino acid levels and balance in critically ill anuric patients on continuous renal replacement therapy.

OBJECTIVES: We wanted to establish optimum protein and glucose intakes during total parenteral nutrition by using a constant caloric but changing protein intake in critically ill, ventilated, anuric patients on continuous renal replacement therapy and measuring amino acid and glucose losses across the hemofilter. METHODS: Eleven consecutive, critically ill patients (eight male, age, 43.5 +/- 21.8 y; Acute Physiology and Chronic Health Evaluation II score, 20.5 +/- 7.0; Acute Physiology and Chronic Health Evaluation risk of death: 36.5% +/- 23.0 and 6 +/- 1 impaired organ systems) entered this study. Patients were fed by continuous infusion of a total parenteral mixture consisting of Synthamin (a mixture of essential and non-essential amino acids), 50% dextrose, and intralipid (long-chain triglycerides) to meet caloric requirements as predicted by Schofield's equation corrected by stress factors. The amount of protein infused was varied (1 to 2.5 g. kg(-1). d(-1)) by increments of 0.25 g. kg(-1). d(-1). Patients were stabilized on each feeding regimen for at least 24 h before paired samples of blood and dialysate were taken for amino acid and glucose measurements. Continuous renal replacement therapy was performed by using a blood pump with a blood flow of 100 to 175 mL/min. Dialysate was pumped in and out counter-currently to the blood flow at 2 L/h. A biocompatible polyacrylonitrile hemofilter was used in all cases. RESULTS: With protein intakes below 2.5 g. kg(-1). d(-1), blood levels of 14% to 57% of the measured amino acids were below the lower limits of the normal range. At 2.5 g. kg(-1). d(-1), all measured amino acids were within the normal range. Amino acid balance became more positive as protein input increased (P = 0.0001). Glucose and amino acid losses were dependent on blood concentration. Overall, 17% (range, 13% to 24%) of infused amino acids and 4% of infused glucose were lost in the dialysate. CONCLUSIONS: This study of critically ill, ventilated, anuric patients on continuous renal replacement therapy suggested that increases in protein and glucose are required to account for the increased losses across the hemofilter. A protein intake of 2.5 g. kg(-1). d(-1) appeared to optimize nitrogen balance and correct amino acid deficiencies.

Adult↗

PubMed2002

Kv channel subunit expression in rat pulmonary arteries.

Hypoxic pulmonary vasoconstriction (HPV) is a mechanism whereby capillary perfusion is modulated to match alveolar ventilation by diverting blood flow away from poorly ventilated regions of the lung. K+ channels, sensitive to changes in oxygen tension, are thought to play a pivotal role in initiating contraction of pulmonary arterial smooth muscle cells. However, the specific channel subtypes involved have not yet been identified. Using RT-PCR, we have investigated the expression of delayed rectifying (Kv) channel mRNA in rat main and small pulmonary arteries and, for comparison, the systemic mesenteric artery. We have identified and fully sequenced a rat Kv9.2 cDNA and also demonstrated the presence of Kv1.7 and Kv4.1. The presence and relative distribution of Kv1.2, Kv1.5, Kv2.1, and Kv9 mRNA is consistent with the proposed contribution of these subunits to oxygen sensing by K channels, previously described in pulmonary arteries. Our data addresses the controversy relating to the likely distribution of Kv channels involved in oxygen sensing without necessarily implying that such subunits are directly responsible for this process. The differential expression of other subunits, particularly Kv4, indicates that these too may have a role in HPV, revealing the need for further biophysical evaluation of these channel subtypes.

Animals↗

PubMed2002

Interactions of platelets with Synthocytes, a novel platelet substitute.

A platelet substitute, Synthocytes, is being developed for the prevention and treatment of thrombocytopenia. Synthocytes are composed of fibrinogen adsorbed on heat stabilised albumin microcapsules of defined size. The purpose of this study was to perform experiments in vitro to investigate the capacity of Synthocytes to interact with platelets, one of the means through which Synthocytes may contribute to haemostatic plug formation in vivo. Synthocytes were found to interact with platelets as shown by platelet aggregation assays and measurements of [(14)C]5HT release from platelets in whole blood and platelet-rich plasma. Platelet-Synthocytes co-aggregate formation was demonstrated directly using flow cytometry and the presence of activated platelets in these co-aggregates was demonstrated using an antibody to P-selectin. Synthocytes enhanced platelet responsiveness to conventional aggregating agents such as ADP. Indeed, antagonists of the action of ADP on platelets inhibited the direct effects of Synthocytes on platelets in whole blood, as did a GPIIb/IIIa antagonist. Enhancement of annexin V binding was also observed, indicative of increased pro-coagulant activity. Experiments performed with control microcapsules (lacking fibrinogen) confirmed the importance of fibrinogen in the interactions that occurred. The results suggest that fibrinogen on the surface of Synthocytes can interact with GPIIb/IIIa on platelets to induce platelet activation, secretory activity and aggregation, and that ADP contributes to this process. This initial interaction renders platelets more susceptible to the stimulatory effects of other platelet-activating agents. It is considered likely that in the clinical setting of thrombocytopenia any interaction between Synthocytes and residual platelets that are present may contribute to primary haemostasis.

Adenosine Diphosphate↗

PubMed2001

Identification of the glycosylation sites utilized on the V1a vasopressin receptor and assessment of their role in receptor signalling and expression.

Most of the large family of G-protein-coupled receptors (GPCRs) possess putative N-glycosylation sites within their N-termini. However, for the vast majority of GPCRs, it has not been determined which, if any, of the consensus glycosylation sites are actually utilized or what the functional ramifications are of modification by oligosaccharide. The occurrence and function of glycosylation of the V(1a) vasopressin receptor (V(1a)R) has been investigated in this study. Using a combination of translation systems that are either glycosylation-competent or do not support glycosylation, we established that of the four putative N-glycosylation sites at Asn(14), Asn(27), Asn(198) and Asn(333) only the first three sites are actually modified by carbohydrate. This was confirmed by disruption of consensus sites by site-directed mutagenesis, individually and in combination. The V(1a)R is not O-glycosylated. The functionality of a series of glycosylation-defective V(1a)R constructs was characterized after expression in HEK 293T cells. It was found that carbohydrate moieties are not required for the receptor to bind any of the four classes of ligand available, or for intracellular signalling. The glycosylation status of the V(1a)R did, however, regulate the level of total receptor expression and also the abundance of receptor at the cell surface. Furthermore, the nature of this regulation (increased or decreased expression) was dictated by the locus of the oligosaccharide modification. Modification of any one of the consensus sites alone, however, was sufficient for wild-type expression, indicating a redundancy within the glycosylation sites. A role for the carbohydrate in the correct folding or stabilization of the V(1a)R is indicated. Glycosylation is not required, however, for efficient trafficking of the receptor to the cell surface. This study establishes the functional importance of N-glycosylation of the V(1a)R.

Amino Acid Sequence↗

PubMed2001

Evidence-based medicine in intensive care.

The life-threatening nature of critical illness, requiring simultaneous, multiple interventions, makes it difficult, if not impossible, to study the effects of any one treatment. It is often not possible to conduct trials in critically ill patients, as they can not give informed consent. Some high quality, prospective studies have influenced clinical practice in intensive care, but others with lower grades of evidence have led to some controversy. In intensive care, clinical practice is still influenced by a combination of theory, experience and evidence.

Aged↗

PubMed2001

[3H]-Methyllycaconitine: a high affinity radioligand that labels invertebrate nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors (nAChR) of insect and other invertebrates are heterogeneous and new tools are needed to dissect their multiplicity. [(3)H]-Methyllycaconitine ([(3)H]-MLA) is a novel radioligand which is a potent antagonist at vertebrate alpha7-type nAChR. Putative invertebrate nAChR of the aphid Myzus persicae, the moths Heliothis virescens and Manduca sexta, the fly Lucilia sericata, and the squid Loligo vulgaris were investigated in radioligand binding studies with [(3)H]-MLA. Saturable binding was consistent with a single class of high affinity binding sites for each of these invertebrates, characterised by a dissociation constant, K(d), of approximately 1 nM and maximal binding capacities, B(max), between 749 and 1689 fmol/mg protein for the insects and 14,111 fmol/mg protein for squid. [(3)H]-MLA binding to M. persicae membranes was characterised in more detail. Kinetic analysis demonstrated rapid association in a biphasic manner and slow, monophasic dissociation. Displacement studies demonstrate the nicotinic character of [(3)H]-MLA binding sites. Data for all nicotinic ligands, except MLA itself, are consistent with displacement from a high and a low affinity site, indicating that displacement is occurring from two or more classes of nicotinic binding site that are not distinguished by MLA itself. Autoradiographic analysis of the distribution of [(3)H]-MLA binding sites in Manduca sexta shows discrete labelling of neuropil areas of the optic and antennal lobes.

Aconitine↗

PubMed2001

High lactate predicts the failure of intraaortic balloon pumping after cardiac surgery.

BACKGROUND: Despite the use of intraaortic balloon pump (IABP) support in complex cardiac surgical patients, morbidity and mortality rates are high. More advanced mechanical cardiovascular support should be considered in those patients who are highly likely to die despite IABP support. We sought to identify early, readily available prognostic markers for patients receiving IABP support. METHODS: A retrospective analysis was performed on 39 patients requiring IABP support following cardiac surgery for more than 2 years. The accuracy and predictive ability of multiple potential markers of mortality were statistically assessed. RESULTS: Sixty-seven percent of the patients were successfully weaned from IABP support and 46% survived to hospital discharge. Serious complications occurred in 13% of patients. Serum lactate more than 10 mmol/L in the first 8 hours of IABP support predicted a 100% mortality. Base deficit more than 10 mmol/L, mean arterial pressure less than 60 mm Hg, urine output less than 30 mls/h for 2 hours, and dose of epinephrine or norepinephrine more than 10 microg/min were other highly predictive prognostic markers. CONCLUSIONS: Morbidity and mortality rates remain high despite IABP support following cardiac surgery. Mortality can be predicted by the presence of elevated serum lactate, elevated base deficit, hypotension, oliguria and large vasopressor doses, any of which should prompt appropriate consideration as to other mechanical cardiovascular support.

Aged↗

PubMed2000

Using root cause analysis to address patient satisfaction and other improvement opportunities.

BACKGROUND: Despite the considerable attention that health care organizations are devoting to the measurement of patient satisfaction, there is often confusion about how to systematically use these data to improve an organization's performance. A model to use in applying traditional quality improvement methods and tools to patient satisfaction problems includes five primary steps: (1) identifying opportunities, (2) prioritizing opportunities, (3) conducting root cause analysis, (4) designing and testing potential solutions, and (5) implementing the proposed solution. PATIENT SATISFACTION SURVEYS: A satisfaction survey serves best as a high-level screening device, not as a tool to provide highly detailed information about the root causes of patient dissatisfaction. The primary purpose of the survey in the model is to identify improvement opportunities and areas of significant improvement or deterioration. Secondary tools such as brief patient interviews or focus groups may better serve to probe intensively into the problem areas identified by the survey. These tools allow for a direct dialog with the patient to uncover root causes of dissatisfaction and establish potential solutions. DISCUSSION: Although the primary focus of this model has been patient satisfaction issues, the basic steps could easily be applied to virtually any improvement opportunity. Improvement teams should commit to a schedule of 90-minute weekly meetings for 7 weeks. The model, a simple translation of traditional improvement methods and tools to address the unique issues facing patient satisfaction improvement teams, can save improvement teams considerable time, resources, and frustration as they design and launch initiatives to improve patient satisfaction.

Causality↗

PubMed1999

Endothelial cells freshly isolated from resistance-sized pulmonary arteries possess a unique K(+) current profile.

We have, for the first time, developed a reliable method for freshly isolating viable endothelial cells from resistance-sized rat pulmonary arteries. The endothelial origin of these cells was confirmed using indirect immunofluorescence, utilizing fluorescently labeled low-density lipoprotein. Biophysical and pharmacological patch-clamp experiments conducted under quasiphysiological cationic gradients revealed that these cells had a mean resting membrane potential of approximately -38 mV and displayed a delayed-rectifying K(+) current. Immunohistochemical staining of rat lung cross-sections revealed an abundance of K(V)1.5 channel protein in pulmonary endothelium. This is the first report of a delayed-rectifying K(+) current in endothelial cells of resistance-sized pulmonary arteries. Since changes in membrane potential associated with K(+) channel activity affect release of vasoactive substances from endothelial cells, this finding has important implications for understanding the mechanisms underlying control of pulmonary vascular tone.

Animals↗

PubMed1999

Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine receptors.

Methyllycaconitine (MLA), a norditerpenoid alkaloid isolated from Delphinium seeds, is one of the most potent non-proteinacious ligands that is selective for alpha bungarotoxin-sensitive neuronal nicotinic acetylcholine receptors (nAChR). [3H]MLA bound to rat brain membranes with high affinity (Kd = 1.86 +/- 0.31 nM) with a good ratio of specific to non-specific binding. The binding of [3H]MLA was characterised by rapid association (t 1/2 = 2.3 min) and dissociation (t 1/2 = 12.6 min) kinetics. The radioligand binding displayed nicotinic pharmacology, consistent with an interaction with alpha bungarotoxin-sensitive nAChR. The snake alpha-toxins, alpha bungarotoxin and alpha cobratoxin, displaced [3H]MLA with high affinity (Ki = 1.8 +/- 0.5 and 5.5 +/- 0.9 nM, respectively), whereas nicotine was less potent (Ki = 6.1 +/- 1.1 microM). The distribution of [3H]MLA binding sites in crudely dissected rat brain regions was identical to that of [125I] alpha bungarotoxin binding sites, with a high binding site density in hippocampus and hypothalamus, but low density in striatum and cerebellum. [3H]MLA also labelled a sub-population of binding sites which are not sensitive to the snake alpha toxins, but which did not differ significantly from the major population with respect to their other pharmacological properties or regional distribution. [3H]MLA, therefore, is a novel radiolabel for characterising alpha 7-type nAChR. A good signal to noise ratio and rapid binding kinetics provide advantages over the use of radiolabelled alpha bungarotoxin for rapid and accurate equilibrium binding assays.

Aconitine↗

PubMed1999

Understanding patient willingness to recommend and return: a strategy for prioritizing improvement opportunities.

BACKGROUND: Beginning in April 1995, an ongoing, comprehensive measurement system has been developed and refined at BJC Health System, a regional integrated delivery and financing system serving the St Louis metropolitan area, mid-Missouri, and Southern Illinois, to assess patient satisfaction with inpatient treatment, outpatient treatment, outpatient surgery, and emergency care. This system has provided the mechanism for identifying opportunities, setting priorities, and monitoring the impact of improvement initiatives. METHODS: Satisfaction with key components of the care process among 23,361 patients (7,083 inpatients, 8,885 patients undergoing outpatient tests/procedures, 5,356 patients undergoing outpatient surgery, and 2,037 patients receiving emergency care) at 15 BJC Health System facilities was assessed through weekly surveys administered in April 1995 through December 1996. RESULTS: Structural equation models were developed to identify the key predictors of patient advocation-willingness to return for or recommend care. Across all venues of care the compassion provided to patients had the strongest relationship to patient advocation. Within each venue of care, however, a slightly different set of secondary factors emerged. The resulting models provided important information to help prioritize competing improvement opportunities in BJC Health System. In one hospital, a general medicine unit working for several years with little success to improve its patient satisfaction decided to focus on two primary factors predicting patient advocation: nursing care delivery and compassionate care. Root cause analysis was used to determine why two items-staff willingness to help with questions/concerns and clear explanation about tests and procedures-were rated low. On the basis of feedback from phone interviews with discharged patients, the care delivery process was changed to encourage patients to ask questions. Across the next two quarters, this unit experienced significant improvements in both targeted items. DISCUSSION: The significance of compassionate care and care delivery again speaks not only to the importance of the technical quality of clinical care but also to the customer-focused way in which this care was provided. After the primary predictors of patient advocation were identified, management was able to strategically focus improvement initiatives to maximize their impact. Across the organization, improvement teams scanned their data to find key factors where performance was lacking. Once these key opportunities were identified, the teams developed potential solutions and launched initiatives to improve their performance. SUMMARY AND CONCLUSIONS: Results suggest that some core issues are of extreme importance to patients regardless of whether they are receiving care in an inpatient, outpatient, or emergency setting. The compassion with which care is provided appears to be the most important factor in influencing patient intentions to recommend/return, regardless of the setting in which care is provided.

Factor Analysis, Statistical↗

PubMed1999

An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain.

[3H]-Methyllycaconitine ([3H]-MLA) is a new radioligand with selectivity for alpha7-type neuronal nicotinic acetylcholine receptors (nAChRs). In our previous study [Davies, A.R.L., Hardick, D.J., Blagbrough, I.S., Potter, B.V.L., Wolstenholme, A.J. & Wonnacott, S. (1999) Neuropharmacology, 38, 679-690], this radioligand labelled a single class of site in rat brain membranes; its pharmacology and distribution in crudely dissected brain regions closely paralleled that of the well-established alpha7-ligand [125I]-alpha-bungarotoxin. However, a small population of [3H]-MLA binding sites was apparently insensitive to alpha-bungarotoxin. Here we have extended the study to mouse brain, using autoradiography to examine the distribution of [3H]-MLA and [125I]-alpha-bungarotoxin binding sites. [3H]-MLA labelled a single class of site in mouse brain membranes with a KD of 2.2 nM and a Bmax of 45.6 fmol/mg protein. Specific binding, defined by unlabelled MLA (Ki = 0.69 nM), was completely inhibited by (-)-nicotine (Ki = 1.62 microM), whereas alpha-bungarotoxin inhibited only 85% of specific binding (Ki = 3.5 nM). The distributions of [125I]-alpha-bungarotoxin and [3H]-MLA binding sites were compared by autoradiography, and binding was quantitated in 72 brain regions. Binding of both radioligands was highly correlated, with highest densities in the dorsal tegmental nucleus of the pons, colliculi and hippocampus. Serial sections labelled with [3H]-MLA in the absence or presence of unlabelled MLA or alpha-bungarotoxin provided no evidence for any alpha-bungarotoxin-resistant binding. The results are discussed in terms of binding sites that are inaccessible to alpha-bungarotoxin in membrane preparations. This study demonstrates the utility of [3H]-MLA for characterization of alpha7-type nicotinic receptors in mammalian brain, and suggests that it labels a population identical to that defined by [125I]-alpha-bungarotoxin.

Aconitine↗

PubMed1997