Can we reduce disease burden from osteoarthritis?

♦ The comparison of disparate interventions for the prevention and management of osteoarthritis (OA) is limited by the quality and quantity of published efficacy studies and the use of disparate measures for reporting clinical trial outcomes.

♦ The “transfer to utility” technique was used to translate published trial outcomes into a health-related quality-of-life (utility) scale, creating a common metric which supported comparisons between disparate interventions.

♦ Total hip replacement (THR) and total knee replacement (TKR) surgery were the most effective treatments and also highly cost-effective, at estimated cost per quality-adjusted life-year (QALY) of $7500 for THR and $10 000 for TKR (best estimate).

♦ Other apparently highly cost-effective interventions were exercise and strength training for knee OA (< $5000/QALY), knee bracing, and use of capsaicin or glucosamine sulfate (< $10 000/QALY).

♦ The cost per QALY estimates of non-specific and COX-2 inhibitor non-steroidal anti-inflammatory drugs were affected by treatment-related deaths and highly sensitive to the discounting of life-years lost.

♦ OA interventions that have been shown to be ineffective (eg, arthroscopy) are targets for redistribution of healthcare resources.

♦ OA interventions which lack efficacy studies (eg, prevention programs) require further research to assist priority setting.

♦ The application of the Health-sector Wide model to OA demonstrates its role as an evidence-based model that can be successfully applied to identify marginal interventions — those to be expanded and contracted to reduce the expected burden of disease, within current healthcare resources.

Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10

The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4‘ in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM–10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P'-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1' pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1' pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.

Expression of the disintegrin metalloprotease ADAM-10 in prostate cancer and its regulation by dihydrotestosterone, insulin like growth factor -1 and epidermal growth factor in the prostate cell model LNCaP

Purpose: The disintegrin metalloprotease ADAM-10 is a multidomain metalloprotease that is potentially significant in tumor progression due to its extracellular matrix-degrading properties. Previously, ADAM-10 mRNA was detected in prostate cancer (PCa) cell lines; however, the presence of ADAM-10 protein and its cellular localization, regulation, and role have yet to be described. We hypothesized that ADAM-10 mRNA and protein may be regulated by growth factors such as 5α-dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor, known modulators of PCa cell growth and invasion.

Experimental Design: ADAM-10 expression was analyzed by in situ hybridization and immunohistochemistry in prostate tissues obtained from 23 patients with prostate disease. ADAM-10 regulation was assessed using quantitative reverse transcription-PCR and Western blot analysis in the PCa cell line LNCaP.

Results: ADAM-10 expression was localized to the secretory cells of prostate glands, with additional basal cell expression in benign glands. ADAM-10 protein was predominantly membrane bound in benign glands but showed marked nuclear localization in cancer glands. By Western blot, the 100-kDa proform and the 60-kDa active form of ADAM-10 were synergistically up-regulated in LNCaP cells treated with insulin-like growth factor I plus 5α-dihydrotestosterone. Epidermal growth factor also up-regulated both ADAM-10 mRNA and protein.

Conclusions: This study describes for the first time the expression, regulation, and cellular localization of ADAM-10 protein in PCa. The regulation and membrane localization of ADAM-10 support our hypothesis that ADAM-10 has a role in extracellular matrix maintenance and cell invasion, although the potential role of nuclear ADAM-10 is not yet known.

Microwave-accelerated 1,3-dipolar cycloaddition for the formation of fused [n]polynorbornanes

Microwave irradiation induces the 1,3-dipolar cycloaddition of cyclobutane epoxides with norbornenes to afford [n]polynorbornane scaffolds. Greatly enhanced reaction rates and significantly reduced levels of decomposition were observed.

Flock inspired area coverage using wireless boid-like sensor agents

Simulated flocking is achievable using three boid rules [13]. We propose an area coverage model inspired by Reynolds’ flocking algorithm, investigating strategies for achieving quality coverage using flocking rules. Our agents are identical and autonomous, using only local sensory information for indirect communication. Upon deployment, agents are in the default separation mode. The cohesion rule would then guarantee that agents remain within the swarm, covering spaces with explored neighbour spaces. Four experiments are conducted to evaluate our model in terms of coverage quality achieved. We firstly investigate agents’ separation speed before the speed with which isolated agents re-organizes is investigated. The third experiment compares coverage quality achieved using our model with coverage quality achieved using random guessing. Finally, we investigate fault tolerance in the event of agents’ failures. Our model exhibits good separation and cohesion speed, achieving high quality coverage. Additionally, the model is fault tolerant and adaptive to agents’ failures.

Richard Tucker. Deakin University

Creativity has been defined 'as the production of novel and useful ideas in any domain'. I would question the words 'novel' and 'useful' because, if the idea is 'useless' but new to the creator, the creator has still given birth to an idea via some form of creative process. I suggest, therefore, that 'creativity' is simply the production of ideas. But it is not quite that straightforward. Innovation is often distinguished from creativity as the successful implementation of ideas. Yet there is a creative process between the birth of an idea and its implementation—that is evolving/ developing/ operating on an idea. This development of an idea is also creativity. I would therefore say that creativity is a two-stage process: it is, firstly, the production and, secondly, the development of ideas; where 'production' is understood as the initiating activities a designer undertakes to inform or inspire ideas.