Bone and Joint Diseases: Prevention and Control

Arthritis is Australia's major cause of disability and chronic pain. In Australian women, osteoarthritis is the third leading cause of years lost due to disability. Osteoporosis affects nearly two million Australians. The Federal government acknowledged the importance of musculoskeletal diseases by designating arthritis and musculoskeletal diseases as the seventh National Health Priority. This decade has been designated by the United Nations and the World Health Organization as the Decade of Bone and Joint Disease. To try to raise awareness, the National Action Network (the committee charged with organising activities in Australia) arranged a summit in 2002 to focus on preventive issues for osteoporosis and arthritis, and the benefits of surgical approaches

Dynamical Dark Matter: II. An Explicit Model

In a recent paper (arXiv:1106.4546), we introduced "dynamical dark matter," a new framework for dark-matter physics, and outlined its underlying theoretical principles and phenomenological possibilities. Unlike most traditional approaches to the dark-matter problem which hypothesize the existence of one or more stable dark-matter particles, our dynamical dark-matter framework is characterized by the fact that the requirement of stability is replaced by a delicate balancing between cosmological abundances and lifetimes across a vast ensemble of individual dark-matter components. This setup therefore collectively produces a time-varying cosmological dark-matter abundance, and the different dark-matter components can interact and decay throughout the current epoch. While the goal of our previous paper was to introduce the broad theoretical aspects of this framework, the purpose of the current paper is to provide an explicit model of dynamical dark matter and demonstrate that this model satisfies all collider, astrophysical, and cosmological constraints. The results of this paper therefore constitute an "existence proof" of the phenomenological viability of our overall dynamical dark-matter framework, and demonstrate that dynamical dark matter is indeed a viable alternative to the traditional paradigm of dark-matter physics. Dynamical dark matter must therefore be considered alongside other approaches to the dark-matter problem, particularly in scenarios involving large extra dimensions or string theory in which there exist large numbers of particles which are neutral under Standard-Model symmetries.Comment: 45 pages, LaTeX, 10 figures. Replaced to match published versio

Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer.

The introduction of serum Prostate Specific Antigen (PSA) testing nearly 30 years ago has been associated with a significant shift towards localized disease and decreased deaths due to prostate cancer. Recognition that PSA testing has caused over diagnosis and over treatment of prostate cancer has generated considerable controversy over its value, and has spurred efforts to identify prognostic biomarkers to distinguish patients who need treatment from those that can be observed. Recent studies show that cancer is heterogeneous and forms a hierarchy of tumor cell populations. We developed a method of identifying prostate cancer differentiation states related to androgen signaling using Boolean logic. Using gene expression data, we identified two markers, CD38 and ARG2, that group prostate cancer into three differentiation states. Cancers with CD38-, ARG2- expression patterns, corresponding to an undifferentiated state, had significantly lower 10-year recurrence-free survival compared to the most differentiated group (CD38+ARG2+). We carried out immunohistochemical (IHC) staining for these two markers in a single institution (Stanford; n = 234) and multi-institution (Canary; n = 1326) cohorts. IHC staining for CD38 and ARG2 in the Stanford cohort demonstrated that combined expression of CD38 and ARG2 was prognostic. In the Canary cohort, low CD38 protein expression by IHC was significantly associated with recurrence-free survival (RFS), seminal vesicle invasion (SVI), extra-capsular extension (ECE) in univariable analysis. In multivariable analysis, ARG2 and CD38 IHC staining results were not independently associated with RFS, overall survival, or disease-specific survival after adjusting for other factors including SVI, ECE, Gleason score, pre-operative PSA, and surgical margins

Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient therapeutic effect. We assessed the ability of a peptide based, oligonucleotide condensing, endosomolytic nanoparticle (NP) system to deliver siRNA to KRAS-driven cancers. We show that this peptide-based NP is avidly taken up by cancer cell

Imaging nuclear, endoplasmic reticulum, and plasma membrane events in real time

Live cell imaging can provide important information on cellular dynamics; however, the full utilisation of this technology has been hampered by the limitations of imaging reagents. Metal-based complexes have the potential to overcome many of the issues common to many current imaging agents. The rhenium (I)-based complex fac-[Re(CO)3(1,10-phenanthroline)(4-pyridyltetrazolate)], herein referred to as ReZolve-ER™, shows promise as a live cell imaging agent with rapid cell uptake, low cytotoxicity, resistance to photobleaching and compatibility with multicolour imaging. ReZolve-ER™ localised to the nuclear membrane/endoplasmic reticulum (ER) and allowed the detection of exocytotic events at the plasma membrane. Thus, we present a new imaging agent for monitoring live cell events in real time, which is ideal for imaging either short- or long-time courses

Ami - The Chemist's Amanuensis

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract The Ami project was a six month Rapid Innovation project sponsored by JISC to explore the Virtual Research Environment space. The project brainstormed with chemists and decided to investigate ways to facilitate monitoring and collection of experimental data. A frequently encountered use-case was identified of how the chemist reaches the end of an experiment, but finds an unexpected result. The ability to replay events can significantly help make sense of how things progressed. The project therefore concentrated on collecting a variety of dimensions of ancillary data - data that would not normally be collected due to practicality constraints. There were three main areas of investigation: 1) Development of a monitoring tool using infrared and ultrasonic sensors; 2) Time-lapse motion video capture (for example, videoing 5 seconds in every 60); and 3) Activity-driven video monitoring of the fume cupboard environs. The Ami client application was developed to control these separate logging functions. The application builds up a timeline of the events in the experiment and around the fume cupboard. The videos and data logs can then be reviewed after the experiment in order to help the chemist determine the exact timings and conditions used. The project experimented with ways in which a Microsoft Kinect could be used in a laboratory setting. Investigations suggest that it would not be an ideal device for controlling a mouse, but it shows promise for usages such as manipulating virtual molecules.Peer Reviewe

Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies

Extending the Real-Time Maude Semantics of Ptolemy to Hierarchical DE Models

This paper extends our Real-Time Maude formalization of the semantics of flat Ptolemy II discrete-event (DE) models to hierarchical models, including modal models. This is a challenging task that requires combining synchronous fixed-point computations with hierarchical structure. The synthesis of a Real-Time Maude verification model from a Ptolemy II DE model, and the formal verification of the synthesized model in Real-Time Maude, have been integrated into Ptolemy II, enabling a model-engineering process that combines the convenience of Ptolemy II DE modeling and simulation with formal verification in Real-Time Maude.Comment: In Proceedings RTRTS 2010, arXiv:1009.398

Changes in longer consultations for children in general practice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97524/1/jpc12157.pd

Prospects for local co-governance

British local authorities and their partners are increasingly developing new ways of working together with local communities. The nature of this co-working, however, is complex, multi-faceted and little understood. This article argues for greater clarity of thinking on the topic, by analysing this co-working as a form of political co-governance, and drawing attention in particular to issues of scale and democracy. Using evidence from a study of 43 local authority areas, 16 authorities are identified where co-governance is practised, following three main types of approach: service-influencing, service-delivering and parish council developing. It is concluded that strengthening political co-governance is essential for a healthy democracy