Using general practice clinical information system data for research: the case in Australia.

General practice is often a patient's first point of contact with the health system and the gateway to specialist services. In Australia, different aspects of the health system are managed by the Commonwealth Government and individual state / territory governments. Although there is a long history of research using administrative data in Australia, this split in the management and funding of services has hindered whole-system research. Additionally, the administrative data typically available for research are often collected for reimbursement purposes and lack clinical information. General practices collect a range of patient information including diagnoses, medications prescribed, results of pathology tests ordered and so on. Practices are increasingly using clinical information systems and data extraction tools to make use of this information. This paper describes approaches used on several research projects to access clinical, as opposed to administrative, general practice data which to date has seen little use as a resource for research. This information was accessed in three ways. The first was by working directly with practices to access clinical and management data to support research. The second involved accessing general practice data through collaboration with Primary Health Networks, recently established in Australia to increase the efficiency and effectiveness of health services for patients. The third was via NPS MedicineWise's MedicineInsight program, which collects data from consenting practices across Australia and makes these data available to researchers. We describe each approach including data access requirements and the advantages and challenges of each method. All approaches provide the opportunity to better understand data previously unavailable for research in Australia. The challenge of linking general practice data to other sources, currently being explored for general practice data, is discussed. Finally, we describe some general practice data collections used for research internationally and how these compare to collections available in Australia.

cisRED: a database system for genome-scale computational discovery of regulatory elements.

We describe cisRED, a database for conserved regulatory elements that are identified and ranked by a genome-scale computational system (www.cisred.org). The database and high-throughput predictive pipeline are designed to address diverse target genomes in the context of rapidly evolving data resources and tools. Motifs are predicted in promoter regions using multiple discovery methods applied to sequence sets that include corresponding sequence regions from vertebrates. We estimate motif significance by applying discovery and post-processing methods to randomized sequence sets that are adaptively derived from target sequence sets, retain motifs with p-values below a threshold and identify groups of similar motifs and co-occurring motif patterns. The database offers information on atomic motifs, motif groups and patterns. It is web-accessible, and can be queried directly, downloaded or installed locally.

Serial analysis of gene expression in the southern cattle tick following acaricide treatment of larvae from organophosphate resistant and susceptible strains.

Organophosphate resistant and susceptible tick larvae from laboratory strains of the southern cattle tick, Rhipicephalus (Boophilus) microplus were exposed to low doses of the organophosphate (OP) acaricide, coumaphos. Serial analysis of gene expression (SAGE) was used to analyse differential gene expression in response to OP treatment and to compare the responses of OP-treated and -untreated resistant and susceptible tick larvae. An R. microplus Gene Index was used as an EST database to identify genes which corresponded to SAGE tags whose abundance changed in response to acaricide exposure. Relative quantitative RT-PCR was used to confirm the differential expression results from the SAGE experiments. Of particular interest is a SAGE tag which corresponds to a cytochrome P450-like EST in the Gene Index which was more abundant in untreated OP resistant larvae compared to untreated OP susceptible larvae. This SAGE tag was also more abundant in OP resistant larvae treated with OP compared to OP susceptible larvae treated with OP.

Kinetics of thapsigargin-Ca(2+)-ATPase (sarcoplasmic reticulum) interaction reveals a two-step binding mechanism and picomolar inhibition.

Thapsigargin is a high affinity inhibitor of sarco- and endoplasmic reticulum (SERCA) type ATPases. We have used kinetics to determine the dissociation constant of thapsigargin-sarcoplasmic reticulum Ca(2+)-ATPase interaction in the absence and presence of non-ionic detergent. The observed "off" rate constant was measured as 0.0052 s-1 at 26 degrees C by the kinetics of inhibition of ATPase activity following transfer from an inactivated thapsigargin-ATPase complex to native ATPase. Inactive ATPase was produced by cross-linking the active site with glutaraldehyde. The observed dissociation rate constant was increased 7-fold by 0.1% Triton X-100, indicating that perturbation of the transmembrane and stalk region by detergent altered the binding parameters of the inhibitor. In addition, thapsigargin stabilized the ATPase against inactivation caused by detergent in the absence of Ca2+. The observed "on" rate constant of thapsigargin was measured at 26 degrees C as 25 s-1 irrespective of thapsigargin concentration, by the kinetics of thapsigargin- induced change in intrinsic fluorescence. An Arrhenius plot showed a temperature dependence of this rate constant, indicative of a conformational change in the protein with an activation energy of 9.5 kcal/mol for thapsigargin binding. The affinity of the Ca(2+)-ATPase for thapsigargin was calculated to be greater than 2 pM at pH 7.0 and 26 degrees C.