Search PubMed⌕ Search

Biomedical subjects

W G Scott

Publications and source records attributed to W G Scott.

At least 37 records · Page 2Linked to original sources
PubMed1996

Capturing the structure of a catalytic RNA intermediate: the hammerhead ribozyme.

The crystal structure of an unmodified hammerhead RNA in the absence of divalent metal ions has been solved, and it was shown that this ribozyme can cleave itself in the crystal when divalent metal ions are added. This biologically active RNA fold is the same as that found previously for two modified hammerhead ribozymes. Addition of divalent cations at low pH makes it possible to capture the uncleaved RNA in metal-bound form. A conformational intermediate, having an additional Mg(II) bound to the cleavage-site phosphate, was captured by freeze-trapping the RNA at an active pH prior to cleavage. The most significant conformational changes were limited to the active site of the ribozyme, and the changed conformation requires only small additional movements to reach a proposed transition-state.

Base Sequence↗
PubMed1996

Economic evaluation of vaccination against influenza in New Zealand.

The objective of this study was to evaluate the costs and benefits of influenza vaccination for the population aged 65 years and over, from the perspectives of individuals and health insurers, government and society. The annual incremental direct medical costs and benefits of influenza vaccination (compared with the nonvaccination, or 'do nothing', option) were evaluated using New Zealand healthcare resource usage and unit cost data [in 1992 New Zealand dollars ($NZ); $NZ1 = $US0.5458, June 1992] applied to cohort studies reported in the literature. The costs and benefits to society as a result of vaccination of people aged 65 years and older (20% of people in this age group are currently vaccinated) were estimated to be: (i) additional direct medical costs of vaccination of $NZ1.42 million [$NZ17.78 per vaccination]; (ii) direct medical costs avoided of $NZ5.35 million ($NZ67.18 per vaccination); and (iii) net benefits of $NZ3.93 million ($NZ49.40 per vaccination). The direct medical costs avoided per dollar cost of vaccination were $NZ1.04 for individuals, $NZ4.69 for government and $NZ3.78 for society as a whole. If the vaccination uptake for this group is increased in 20% increments, the net benefit to society increases by a further $NZ3.93 million per year at each step. If the economic evaluation is extended to include vaccination of at-risk individuals under 65 years of age, net benefits to society increase by 15%. Influenza vaccination for people aged 65 years and over is cost effective from the perspective of society, government and the individual. If the vaccination rate for at-risk individuals in New Zealand could be increased to 60%, the net benefits reported in this study would increase by 200%. However, the costs of promotion and education to achieve this vaccination rate would need to be deducted from the net benefits. Strategies to increase the vaccination rate include altering the cost of vaccinations to the individual, intensifying education and promotion programmes, and changing the mode of delivery.

Cost-Benefit Analysis↗
PubMed1996

Heart failure. A decision analytic analysis of New Zealand data using the published results of the SOLVD Treatment Trial. Studies of Left Ventricular Dysfunction.

This study sought to evaluate the changes in direct medical costs and life-years gained or lost by adding enalapril to conventional treatment (digoxin and diuretics) for heart failure (HF). The published results of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial, and a decision analytical model developed by the University of Pennsylvania, were used in combination with New Zealand data to undertake the evaluation. All costs were measured in 1993 New Zealand dollars ($NZ) [$NZ1 = $US0.5509, September 1993]. Potential net cost savings per patient treated over a 4-year period were $NZ652 together with an additional 2 months of life gained. If these individual potential cost savings are extended to the New Zealand population who have HF (but are at present not receiving an ACE inhibitor) then $NZ6 517 000 in discounted health sector costs could be avoided. The model was sensitive to changes in the price of enalapril, to estimates of the population with HF, the percentage of the population with HF treated with enalapril, and to hospital unit costs for nonfatal cases of HF. The study demonstrated that the addition of enalapril to the conventional treatment of HF was cost effective when compared with conventional medical therapy alone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Ribozymes: structure and mechanism in RNA catalysis.

The hammerhead RNA is a small catalytic RNA found in a number of RNA virus genomes and virus-like RNAs. The recently determined crystal structures of hammerhead ribozymes reveal how a small RNA motif can fold up into a conformation suitable for mediating RNA cleavage.

Base Sequence↗
PubMed1995

Hysterectomy for nonmalignant conditions: cost to New Zealand society.

AIMS: The aim of the study was to estimate the annual hospital costs to New Zealand society of hysterectomy for nonmalignant conditions in women between puberty and menopause, and to compare international rates for all hysterectomies. METHODS: The records of patients aged between 15 and 54 years inclusive, who had a hysterectomy for a nonmalignant menstrual condition, were researched. Hospital costs were estimated using specific hospital unit costs and prices. RESULTS: The 4390 hysterectomies for nonmalignant conditions represent 69% of the total hysterectomies undertaken in New Zealand in 1991. Estimated costs for all hospitals were $17 million or $3868 per hysterectomy. The all ages all conditions hysterectomy rate per 100,000 women of 365 (368 in 1992) in New Zealand is higher than in some other developed countries. CONCLUSIONS: Further reduction in the rate of hysterectomy in New Zealand may save hospital costs but these savings should be offset against the costs of any other treatment options chosen. Although it was found that unit costs of public hospitals were higher than those of private hospitals the case mix for the two types of hospital may differ and public hospital cost reductions may not be possible. Economic evaluation of alternative treatment options would be improved if all relevant costs (direct, indirect and intangible) were known. Further research is needed to determine the reasons why New Zealand women elect to have hysterectomies, why most choose a private hospital, and changes (before and after hysterectomy) in productivity, out of pocket expenses, and quality of life for these patients.

Adolescent↗
PubMed1995

Rapid crystallization of chemically synthesized hammerhead RNAs using a double screening procedure.

To find conditions for obtaining diffraction-quality crystals of a hammerhead RNA rapidly and reproducibly, we employed a "double screening" procedure in which we screened six different RNA synthetic constructs against 48 crystallization conditions using a newly devised sparse matrix. We obtained crystals immediately and diffraction-quality crystals of the sixth RNA construct within six months of initiating the screening of additional RNA sequences. The best crystals diffract to 2.9 A resolution when flash-cooled at synchrotron X-ray sources. Solid-support chemical synthesis combined with sparse matrix screening should allow rapid production of diffraction-quality crystals of a variety of small RNAs, reducing the time commitment for initiating such crystallography projects from several years to several months. The synthetic approach also makes introduction of modified bases to prevent self-cleavage and to generate isomorphous heavy-atom derivative crystals a rapid and straightforward process.

Base Sequence↗
PubMed1995

The crystal structure of an all-RNA hammerhead ribozyme: a proposed mechanism for RNA catalytic cleavage.

We have solved the crystal structure of an all-RNA hammerhead ribozyme having a single 2'-O-methyl cytosine incorporated at the active site to prevent cleavage. The conditions used differ from those in another recent solution in four significant ways: first, it is an all-RNA ribozyme rather than a DNA-RNA hybrid; second, the connectivity of the ribozyme backbone strands is different; third, the crystals were grown in the presence of a much lower concentration of salt; and fourth, the crystal packing scheme is very different. Nevertheless, the three-dimensional structure of the all-RNA hammerhead ribozyme is similar to the previous structure. Five potential Mg(II)-binding sites are identified, including one positioned near the ribozyme catalytic pocket. Upon this basis, as well as upon comparisons with the metal-binding sites in the structurally homologous uridine turn of tRNAPhe, we propose a mechanism for RNA catalytic cleavage.

Base Sequence↗
PubMed1995

Mutagenesis and Laue structures of enzyme intermediates: isocitrate dehydrogenase.

Site-directed mutagenesis and Laue diffraction data to 2.5 A resolution were used to solve the structures of two sequential intermediates formed during the catalytic actions of isocitrate dehydrogenase. Both intermediates are distinct from the enzyme-substrate and enzyme-product complexes. Mutation of key catalytic residues changed the rate determining steps so that protein and substrate intermediates within the overall reaction pathway could be visualized.

Binding Sites↗
PubMed1995

Pharmacoeconomic evaluation of roxithromycin versus amoxycillin/clavulanic acid in a community-acquired lower respiratory tract infection study.

A cost-effectiveness study of roxithromycin versus amoxycillin/clavulanic acid using data from a 242 patient multicentre trial in Australia and New Zealand was undertaken in the general practice treatment of infections of the lower respiratory tract (LRTI). Those patients assigned to roxithromycin required on average 1 day less of treatment, significantly fewer extended courses of treatment, and fewer patients experienced side effects considered to be related to the treatment. The cost benefit (difference between the two treatment costs) per clinical success was A$17.04*. By substituting roxithromycin for amoxycillin/clavulanic acid, Australia would save A$ 1.704 million per 100,000 episodes of LRTI. The results demonstrate that savings in direct costs can be achieved by substituting roxithromycin for amoxycillin/clavulanic acid in the treatment of community-acquired LRTI.

Adolescent↗
PubMed1995

The crystal structure of an all-RNA hammerhead ribozyme.

We have solved the crystal structure of an all-RNA hammerhead ribozyme by isomorphous replacement which contains a single 2'-O-methyl-cytosine at the active site to prevent cleavage. We describe the hammerhead RNA structure from a point of view which shows how the structural elements are disposed to bring the active site nucleotide into the catalytic pocket of the ribozyme. Five potential Mg(II) binding sites can be identified in the hammerhead RNA electron density maps. Of these, one is a newly identified metal site positioned near the ribozyme catalytic pocket, and another site corresponds to a Mn(II) site identified in the previous hammerhead RNA structure. We propose a mechanism for RNA catalytic cleavage on the basis of this new metal-binding site, as well as upon comparisons between the catalytic pocket of the hammerhead RNA and the metal-binding sites in the structurally homologous uridine turn of the anticodon loop in tRNAPhe.

Base Sequence↗
PubMed1994

Ischaemic stroke in New Zealand: an economic study.

AIM: To quantify and describe the annual cost of ischaemic stroke to New Zealand society during 1992. METHODS: A prevalence or cross sectional approach employing incremental estimation was used to estimate costs from the perspective of society. The study used unit record hospital and mortality data. RESULTS: Direct costs ranged from $93 million to $140 m and loss of production was between $6 m and $14 m. Total quantified costs were estimated to lie between $99 m and $154 m. Hospital and continuing care costs when combined make up 90% of all quantified costs. CONCLUSION: Ischaemic stroke affects mainly older people many of whom are discharged into the community and require costly community support or continuing care. The combination of an ageing population, increasing survival rates and constant incidence rates will result in a substantial rise in the costs of continuing care and community support. Most of these costs are at present obscured because much of the care provided does not involve money payments and/or data are not recorded and collated on a national basis. Incorrect policy decisions will be made if the nonhospital costs of stroke are not taken into account.

Adolescent↗
PubMed1994

Transmembrane signalling and the aspartate receptor.

BACKGROUND: The aspartate receptor is a transmembrane protein that mediates bacterial chemotaxis. The structures of the periplasmic ligand-binding domain reveal a dimer, each subunit with four alpha-helix bundles, with aspartate binding to one of two sites at the subunit interface. The transmembrane regions of the receptor were not included in these structures. RESULTS: To investigate the structure of the transmembrane region, we have made a mutant protein with two cross-links, restraining the subunit-subunit interface on both sides of the membrane, and have made an energy-minimized model of the transmembrane region. We demonstrate that the transmembrane helices form a coiled coil which extends from the periplasmic subunit through the membrane. We have constructed a model of the ligand-binding domains with the amino-terminal transmembrane helices. CONCLUSIONS: We draw three conclusions from our model. Firstly, the interface between receptor subunits in the intact receptor consists of an uninterrupted coiled coil. Secondly, this structure rules out several postulated mechanisms of signalling. Thirdly, side chain packing constraints within the helices dictate that local structural changes must be small, but are propagated over a long distance rather than being dissipated locally. Low energy changes in the conformation of side chains are a probable mechanism of signal transduction in the aspartate receptor.

Amino Acid Sequence↗
PubMed1994

Critical leg ischaemia in New Zealand: economic cost of amputation versus intravenous iloprost.

The purpose of this study was to establish the incidence of surgical amputation for critical leg ischaemia in New Zealand, and estimate the hospital, prostheses and indirect costs of this intervention. The cost of amputations was then compared with the cost of treating such patients with iloprost. The study was retrospective. Individual patient records relating to 1991 for both public and private hospitals were analysed. Unit costs relevant to 1991 were applied to the volume data of patients and procedures to derive total costs. Costs were estimated on an incremental basis taking a societal perspective. Conservative estimates were obtained for hospital costs, prostheses and for production loss (loss of output or productivity). Total cost was $NZ15.9 million (hospital and prosthesis cost $NZ13.1 million, production loss $NZ2.8 million). The total quantified cost per amputation was $NZ23 038 (hospital and prosthesis cost $NZ19 020, production loss $NZ4017). 32% of patients requiring amputations were in the working age group. The theoretical avoidance of amputation by treatment with iloprost resulted in net savings of hospital and prosthetic costs of between $NZ6660 and $NZ8720 per patient. Amputation for critical leg ischaemia is costly and has a high mortality, but for iloprost treatment to be cost effective in a New Zealand hospital setting, patients must be targeted and a success rate of at least 55% achieved in avoidance of amputation and reduction of pain while at rest.

Amputation, Surgical↗
PubMed1993

Cost of coronary heart disease in New Zealand.

AIM: To conservatively estimate the costs of coronary heart disease from the perspective of New Zealand society. METHODS: A cross sectional or prevalence analysis (cases and associated costs in one year) was undertaken of the total annual cost of coronary heart disease. Estimates were made on an incremental basis of direct, indirect and intangible costs. Costs relate to 1989 volumes measured in March quarter 1992 dollars (net of goods and services tax). RESULTS: Cost estimates were in all instances conservative values. Direct medical costs amounted to $179 million and indirect costs were between $14 million and $24 million. Loss of life using the human capital approach ranged from $114 million to $264 million, but using the willingness to pay criteria, loss of life was $14,568 million. CONCLUSION: Because of the magnitude of the costs of coronary heart disease even small reductions in the incidence of coronary heart disease will produce substantial savings to society.

Absenteeism↗
PubMed1993

Refined structures of the ligand-binding domain of the aspartate receptor from Salmonella typhimurium.

The aspartate receptor is a transmembrane-signalling protein that mediates chemotaxis behaviour in bacteria. Aspartate receptors in Salmonella typhimurium and Escherichia coli exist as dimers of two subunits in the presence as well as in the absence of aspartate. We have previously reported the three-dimensional structures of the external ligand-binding domain of the S. typhimurium aspartate receptor with and without bound aspartate. The external or periplasmic region of the aspartate receptor is a dimer of four-alpha-helical bundle subunits; a single aspartate molecule binds to one of two sites residing at the subunit interface, increasing the affinity of the subunits for one another. Here we report the results of a detailed analysis of the aspartate receptor ligand-binding domain structure (residues 25 to 188). The dimer interface between the twofold related subunits consists primarily of contacts mediated by the side-chains of the N-terminal helix of each four-alpha-helical bundle subunit. The N-terminal helices pack approximately 20 degrees from parallel as an approximate coiled-coil super-secondary structure. We have refined aspartate receptor ligand-binding domain structures in the presence and in the absence of a bound aromatic compound, 1,10-phenanthroline, to 2.2 A and 2.3 A resolution, respectively, as well as crystal structures in the presence of specifically bound Au(I), Hg(II) and Pt(IV) complex ions at 2.4 A, 3.0 A and 3.3 A resolution, respectively. The possible biological relevance of the aromatic ligand-binding site and the metal ion-binding sites is discussed. The dimer of four-alpha-helical bundle subunits composing the periplasmic region of the S. typhimurium aspartate receptor provides a basis for understanding the results of mutational analyses performed on related chemotaxis transmembrane receptors. The crystal structure analysis provides an explanation for the way in which mutations in the E. coli aspartate receptor affect its binding to the periplasmic maltose-binding protein and how mutations in the more distantly related E. coli Trg chemotaxis receptor affect its binding to the periplasmic ribose and glucose-galactose binding proteins.

Aspartic Acid↗