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Biomedical subjects

R Davey

Publications and source records attributed to R Davey.

At least 19 recordsLinked to original sources
PubMed2006

Setting up chronic disease programs: perspectives from Aboriginal Australia.

OBJECTIVE: To share some perspectives on setting up programs to improve management of hypertension, renal disease, and diabetes in high-risk populations, derived from experience in remote Australian Aboriginal settings. PRINCIPLES: Regular integrated checks for chronic disease and their risk factors and appropriate treatment are essential elements of regular adult health care. Programs should be run by local health workers, following algorithms for testing and treatment, with back up from nurses. Constant evaluation is essential. COMPONENTS: Theses include testing, treatment, education for individuals and communities, skills and career development for staff, ongoing evaluation, program modification, and advocacy. Target groups, elements, and frequency of testing, as well as the reagents and treatment modalities must be designed for local circumstances, which include disease burden and impact, competing priorities, and available resources. Pilot surveys or record reviews can define target groups and conditions. Opportunistic testing will suffice if people are seen with some regularity for other conditions; otherwise, systematic screening is needed, preferably embedded in primary care streams. The chief goal of treatment is to lower blood pressure, and if the patient is diabetic, to control hyperglycemia. Many people will need multiple drugs for many years. CHALLENGES: Challenges include lack of resources, competing demands of acute care, the burden of treatment when disease rates are high, problems with information systems, and in our setting, health worker absenteeism. FUNDING: Businesses, altruistic organizations, and pharmaceutical and biotechnology companies might fund feasibility studies. Where governments or insurance companies already support health services, they must ultimately commit to chronic disease services over the long- term. Effective advocacy requires the presentation of an integrated view of chronic disease and a single cross-disciplinary program for its containment. Arguments based on preserving the economic base of societies by preventing or delaying premature death will carry most weight, as will the costs of dialysis avoided in countries that already support open-access programs.

Adult↗
PubMed2005

Food allergy: gambling your life on a take-away meal.

This study investigates whether or not it is possible to buy meals suitable for peanut allergy sufferers and assesses the training and guidance needs of catering staff and Environmental Health Officers (EHOs) in Northern Ireland with respect to serious food allergies. Meal samples purchased in food premises in the local authority regions of Northern Ireland (NI) were subjected to chemical analysis to check the assertions of the premises staff that they were suitable for peanut allergy sufferers. Officers also assessed if the customer was provided with any information on the allergenic status of foods produced by the establishment; if the EHOs taking the samples had received any training or guidance in allergy-related issues and to gauge the need for such training and guidance. Approximately one in five (13/62) of the premises provided meals which could possibly have triggered a fatal reaction in the purchaser. Most front of house staff did not check the allergen status of the meal with those doing the cooking and most EHOs felt that they needed more training in the subject of food allergen control in commercial food premises. It is important for food allergy sufferers and their medical advisers to be made aware of the limitations of avoidance advice and that false assurances persist of the absence of peanut protein in takeaway foods.

Allergens↗
PubMed2005

Trigeminal cephalgias and facial pain syndromes associated with autonomic dysfunction.

Trigeminal autonomic cephalgias (TACs) include a spectrum of primary headache syndromes associated with cranial autonomic dysfunction. Other types of headache and facial pain syndromes can be associated with marked localized facial or ear autonomic changes. We report on a group of patients suffering from episodic migraine with cranial autonomic features, patients with different presentations of the 'red ear syndrome' (RES), cluster headache with prominent lower facial involvement and crossover cases. In our experience crossover between TACs and migraine, RES and cluster headache is not uncommon. We propose that all these conditions belong to the same group and a unifying causative mechanism is proposed.

Adult↗
PubMed2001

Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport.

OBJECTIVES: To investigate the intracellular accumulation of HIV protease inhibitors (PI) and to assess the effect of active transport on this accumulation. METHODS: CEM cells were incubated with a PI for 18 h and the intracellular concentration determined using cell number and radioactivity. The effect of active transport was investigated using cells expressing P-glycoprotein (CEM(VBL)) and cells expressing multidrug resistance-associated protein 1 (MRP1; CEM(E1000)). Incubations were also carried out at 4 degrees C and in the presence of 2-deoxyglucose plus rotenone to examine the effect of inhibiting active transport. RESULTS: Nelfinavir (NFV) accumulated to the greatest extent (> 80-fold) followed by saquinavir (SQV; approximately 30-fold), ritonavir (RTV; 3-7-fold) and finally indinavir (IDV; extracellular equivalent to intracellular). In CEM(VBL) cells there was a significant reduction in the intracellular accumulation of NFV, SQV and RTV and in CEM(E1000) cells there was reduced accumulation of SQV and RTV. Inhibition of active transport processes caused a reduction in SQV and RTV accumulation but had no effect on IDV accumulation in all cell types. NFV accumulation was increased in CEM(VBL) cells as a result of inhibition of active transport. CONCLUSIONS: Marked differences can be detected in the intracellular accumulation of HIV PI drugs in vitro. Both P-glycoprotein and MRP1 may play a role in limiting the intracellular concentration of the PI and active influx mechanisms may contribute to drug accumulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

The drug resistance proteins, multidrug resistance-associated protein and P-glycoprotein, do not confer resistance to Fas-induced cell death.

BACKGROUND: Multidrug resistance (MDR) is mediated by the drug resistance proteins, the multidrug resistance-associated protein (MRP) and P-glycoprotein, both of which confer resistance by the active efflux of chemotherapeutic drugs from the cell. Reduced Fas (CD95/APO-1) expression and resistance to Fas-mediated apoptosis have also been correlated with P-glycoprotein-mediated MDR. METHODS: We investigated cell surface Fas expression (using anti-Fas monoclonal antibody DX2.1) in a series of MRP-expressing drug-resistant leukemia sublines, and P-glycoprotein-expressing leukemia sublines, and their susceptibility to apoptosis induced by anti-Fas treatment (CH-11 monoclonal antibody). Caspase-3 activation was detected by Western blot and apoptosis was determined by flow cytometry with 7-aminoactinomycin D (7-AAD) staining of cells. RESULTS: Fas expression was not reduced in either the MRP- or P-glycoprotein-expressing drug-resistant cell lines, although expression was reduced by 15% in one low-level drug-resistant subline. Expression of MRP or P-glycoprotein did not confer resistance to caspase-3 activation or to anti-Fas-induced cell death. CONCLUSIONS: MDR mediated by the drug transport proteins MRP and P-glycoprotein does not correlate with resistance to Fas-mediated cell death or resistance to caspase-3 activation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Paclitaxel sensitization of multidrug-resistant cells to chemotherapy is independent of the cell cycle.

BACKGROUND: Recent studies have shown that paclitaxel (Taxol) is an active chemotherapeutic in the treatment of small cell lung cancer. Paclitaxel binds to tubulin and prevents depolymerization. This causes cells to arrest in the G(2)/M phase of the cell cycle, resulting in sensitization of cells to drug or radiation treatment. METHODS: A drug-resistant H69 small cell lung cancer subline was established. Cytotoxicity of cisplatin and chlorambucil was determined using the MTT cell viability assay and distribution of DNA in the cell cycle. DNA distribution was analyzed by flow cytometry after treatment with paclitaxel or the other tubulin-binding drugs, vinblastine and navelbine. RESULTS: The H69-EPR drug-resistant subline was resistant to epirubicin (sixfold) and was cross-resistant to cisplatin (7.5-fold) and chlorambucil (7.5-fold). Pretreatment with paclitaxel or vinblastine, but not navelbine, sensitized the subline to cisplatin and chlorambucil (P < 0.05), with no effect on parental H69 cells. Sensitization was dose dependent and occurred at doses below those that caused a G(2)/M block in the cell cycle. CONCLUSION: Sensitization of drug-resistant cells by paclitaxel was not associated with its ability to cause a G(2)/M block in the cell cycle. Sensitization by paclitaxel and vinblastine, but not navelbine, which preferentially targets mitotic tubulin, suggests that sensitization may involve changes in the tubulin-dependent intracellular transport processes rather than changes in mitotic tubulin and the G(2)/M block.

Amsacrine↗
PubMed2000

The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine.

STUDY OBJECTIVE: To determine the effects of ritonavir on the pharmacokinetics of meperidine and normeperidine. DESIGN: Open-label, crossover, pharmacokinetic study. SETTING: United States government research hospital. SUBJECTS: Eight healthy volunteers who tested negative for the human immunodeficiency virus. INTERVENTION: Subjects received oral meperidine 50 mg and had serial blood samples collected for 48 hours. They then received ritonavir 500 mg twice/day for 10 days, followed by administration of a second 50-mg meperidine dose and collection of serial samples. MEASUREMENTS AND MAIN RESULTS: Plasma samples were assayed for meperidine, normeperidine, and ritonavir. Meperidine's area under the curve (AUC) decreased in all subjects by a mean of 67+/-4% in the presence of ritonavir (p<0.005). Mean +/- SD maximum concentration was decreased from 126+/-47 to 51+/-21 ng/ml. Normeperidine's mean AUC was increased 47%, suggesting induction of hepatic metabolism. CONCLUSION: Meperidine's AUC is significantly reduced, not increased, by concomitant ritonavir. Based on these findings, the risk of narcotic-related adverse effects from this combination appears to be minimal. However, increased concentrations of normeperidine suggest a potential for toxicity with increased dosages or long-term therapy.

Adult↗
PubMed1999

Processing of normal lysosomal and mutant N-acetylgalactosamine 4-sulphatase: BiP (immunoglobulin heavy-chain binding protein) may interact with critical protein contact sites.

The lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4-sulphatase) is essential for the sequential degradation of the glycosaminoglycans, dermatan and chondroitin sulphate and, when deficient, causes the lysosomal storage disorder mucopolysaccharidosis type VI. The cysteine at codon 91 of human 4-sulphatase was identified previously as a key residue in the active site of the enzyme and was mutated by site-directed mutagenesis to produce a 4-sulphatase in which cysteine-91 was replaced by a threonine residue (C91T). The C91T mutation caused a loss of 4-sulphatase activity, a detectable protein conformational change and a lower level of intracellular 4-sulphatase protein [Brooks, Robertson, Bindloss, Litjens, Anson, Peters, Morris and Hopwood (1995) Biochem. J. 307, 457-463]. In the present study, we report that C91T is synthesized normally in the endoplasmic reticulum as a 66 kDa glycosylated protein, which is very similar in size to wild-type 4-sulphatase. However, C91T neither underwent normal Golgi processing, shown by lack of modification to form mannose 6-phosphate residues on its oligosaccharide side chains, nor did it traffic to the lysosome to undergo normal endosomal-lysosomal proteolytic processing. Instead, C91T remained in an early biosynthetic compartment and was degraded. The molecular chaperone, immunoglobulin binding protein (BiP), was associated with newly-synthesized wild-type and mutant 4-sulphatase proteins for extended periods, but no direct evidence was found for involvement of BiP in the retention or degradation of the C91T protein. This suggested that prolonged association of mutant protein with BiP does not necessarily infer involvement of BiP in the quality control process, as previously implied in the literature. The predicted BiP binding sites on 4-sulphatase map to beta-strands and alpha-helices, which are co-ordinated together in the folded molecule, indicating that BiP interacts with critical protein folding or contact sites on 4-sulphatase.

Binding Sites↗
PubMed1997

Lysosomal biogenesis in lysosomal storage disorders.

Lysosomal biogenesis is an orchestration of the structural and functional elements of the lysosome to form an integrated organelle and involves the synthesis, targeting, functional residence, and turnover of the proteins that comprise the lysosome. We have investigated lysosomal biogenesis during the formation and dissipation of storage vacuoles in two model systems. One involves the formation of sucrosomes in normal skin fibroblasts and the other utilizes storage disorder-affected skin fibroblasts; both of these systems result in an increase in the size and the number of lysosomal vacuoles. Lysosomal proteins, beta-hexosaminidase, alpha-mannosidase, N-acetylgalactosamine-4-sulfatase, acid phosphatase, and the lysosome-associated membrane protein, LAMP-1, were shown to be elevated between 2- and 28-fold above normal during lysosomal storage. Levels of mRNA for the lysosome-associated membrane proteins LAMP-1 and LAMP-2, N-acetylgalactosamine-4-sulfatase, and the 46- and 300-kDa mannose-6-phosphate receptors were also elevated 2- to 8-fold. The up-regulation of protein and mRNA lagged 2-4 days behind the formation of lysosomal storage vacuoles. Correction of storage, in both systems, resulted in the rapid decline of the mRNA to basal levels, with a slower decrease in the levels of lysosomal proteins. Lysosomal biogenesis in storage disorders is shown to be a regulated process which is partially controlled at, or prior to, the level of mRNA. Although lysosomal proteins were differentially regulated, the coordination of these events in lysosomal biogenesis would suggest that a common mechanism(s) may be in operation.

Antibodies, Monoclonal↗
PubMed1997

Increasing vancomycin resistance in Enterococcus spp. in Australia: facing the challenge in the laboratory.

High level vancomycin resistance in enterococci (VRE) is increasing in Australia. If the spread of VRE is to be checked, then it is vital for laboratories to be able to detect it promptly and accurately. We have established a rapid and accurate screening method using Enterococcosel agar supplemented with 6 mg/l vancomycin. It can recover VRE from spiked feces, it may be used to screen feces for carriage of VRE and it is not subject to the confounding effects which feces introduce to broth enrichment culture.

Australia↗
PubMed1997

Physical activity for the over-65s: could it be a cost-effective exercise for the NHS?

BACKGROUND: There is increasing interest in the health-promoting potential of physical activity in older adults. The objective of this study was to estimate the likely costs, health benefits and consequences for the National Health Service which might result from a publicly funded programme of regular exercise made available to a population of 10,000 people over the age of 65. METHODS: Risk education data from observational studies were used to calculate the possible impact of a community-based programme of activity on hospital admissions and deaths from coronary heart disease, stroke, diabetes, femoral neck fractures and mental disorders. The avoided costs of health care and net cost per life-year saved were estimated. RESULTS: Providing twice-weekly exercise classes for 10,000 participants would cost approximately 854,700 pounds per year, but would prevent 76 deaths and 230 in-patient episodes, avoiding annual health care costs of approximately 601,000 pounds. Assuming the mean expectation of life after 65 to be ten years, the programme would cost about 330 pounds per life-year saved. Under a range of more extreme assumptions, the cost per life-year saved would vary from 100 pounds to 1500 pounds. CONCLUSIONS: A publicly funded programme of regular moderate exercise for over-65-year-olds could achieve important health benefits at relatively low cost. The estimates provided by this analysis should now be tested in a rigorous randomized trial, and health commissioners should begin to think of purchasing exercise programmes alongside other health-promoting measures.

Aged↗
PubMed1997

Titrated intravenous opioids from the same syringe: an infection risk?

OBJECTIVE: (1) To compare the rate of contamination of syringes prepared under laminar flow conditions in pharmacy with those prepared by nurses in the emergency department; (2) to determine whether the time elapsed since preparation or number of doses given affected the contamination rate; (3) to determine whether any adverse effects resulted from bacterially contaminated drugs. METHODS: Prospective, blinded trial exploring the effect of method of preparation, time since preparation, and number of doses given on contamination rates and infective adverse events associated with bacterially contaminated specimens. RESULTS: The rate of bacterial contamination was 12% (95% confidence interval 6% to 18%). There was no difference in contamination rate in respect of method of preparation, number of doses given, or time since preparation. No infective complications were identified. CONCLUSIONS: Abandonment of titrated intravenous opioids is not justified by the results. However, there is concern about the use of this technique of pain control for immunocompromised patients and those with prosthetic heart valves.

Analgesia↗
PubMed1997

Thyroxine, thyrotropin, and age in a euthyroid hospital patient population.

The diagnosis of thyroid disease now often can be achieved reliably by measuring thyrotropin (TSH) alone. Thyroxine (T4), triiodothyronine, and other analytes are only needed if TSH and the accompanying clinical condition are discordant. We describe here work that confirms the age independence of TSH in both inpatient and outpatient euthyroid hospital populations between ages 20 and at least 80 years, and demonstrates that although free T4 does vary with age, the range of variation remains within the T4 reference interval. On this basis, TSH-based thyroid diagnostic algorithms can be used reliably in adults without reference to age-related reference intervals.

Adolescent↗