Australia's national health programs: An ontological mapping

Australia has a large number of health program initiatives whose comprehensive assessment will help refine and redefine priorities by highlighting areas of emphasis, under-emphasis, and non-emphasis. The objectives of our research are to: (a) systematically map all the programs onto an ontological framework, and (b) systemically analyse their relative emphases at different levels of granularity. We mapped all the health program initiatives onto an ontology with five dimensions, namely: (a) Policy-scope, (b) Policy-focus, (c) Outcomes, (d) Type of care, and (e) Population served. Each dimension is expanded into a taxonomy of its constituent elements. Each combination of elements from the five dimensions is a possible policy initiative component. There are 30,030 possible components encapsulated in the ontology. It includes, for example: (a) National financial policies on accessibility of preventive care for family, and (b) Local-urban regulatory policies on cost of palliative care for individual-aged. Four of the authors mapped all of Australia's health programs and initiatives on to the ontology. Visualizations of the data are used to highlight the relative emphases in the program initiatives. The dominant emphasis of the program initiatives is: [National] [educational, personnel-physician, information] policies on [accessibility, quality] of [preventive, wellness] care for the [community]. However, although (a) information is emphasized technology is not and (b) accessibility and quality are emphasized cost, satisfaction, and quality are not. The ontology and the results of the mapping can help systematically reassess and redirect the relative emphases of the programs and initiatives from a systemic perspective

Nano-Carbides and the Strength of Steels as Assessed by Electrical Resistivity Studies

The work of Frommeyer on electrical conductivity measurements in pearlitic steels is reviewed to provide insight into microstructures developed during wi wire drawing. Electrical re conductivity measurements were made as a function of drawing strain (up to {var_epsilon} = 6.0) for wires with strength exceeding 3500MPa. The results show that electrical conductivity increases during wire wire-drawing to a maximum value, then decreases with further deformation finally reaching a steady state value that is equal to the original conductivity. The initial increase is the result of pearlite plate orientation in the direction of wire wire-drawing, which makes the path of conduction through the ferrite plates more accessible. At a critical strain the cementite plates begin to fragment and the electrical conductivity decreases to a steady state value that is the same as that observed prior to wire drawing. With increasing strain, the cementite particles are refined and the strength increases due to the reduction in inter inter-particle spacing. It is concluded that the electrical conductivity of the wires is solely dependent on the amount of iron carbides provided they are randomly distributed as plates or as particles. An estimate was made that indicates the carbide particle size is approximately 3-5 nm in the steady state range of electrical conductivity

Inhibition of mapk signalling promotes cell cycle arrest and sensitises intrahepatic cholangiocarcinoma cells to chemotherapy

Introduction: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for approximately 15% of cases of primary liver cancer. Although new treatments have increased survival for many other cancers, including the more common primary hepatocellular carcinoma, treatment strategies and survival for patients with ICC have seen little improvement. Our previous studies suggest that the mitogen-activated protein kinase (MAPK) signalling plays a central role in the regulation of cell proliferation in human ICC. However the molecular mechanisms are poorly understood. In this study, we aim to explore whether inhibition of the MAPK pathway and its downstream effectors enhances the sensitisation of ICC cells to the chemotherapeutic agent cisplatinum. Method: We used a combinatorial approach of immunohistochemical and gene expression analyses to investigate the expression of MAPK-related genes in ICC tumours. Furthermore, by using in-vitroand in-vivoanalyses we have characterised the function of a novel MAPK downstream effector in ICC cells. Results: The expression of MAPK signalling was determined by immunohistochemical staining in tumour samples from a cohort of 14 ICC patients. High expression of phospho-activated MAPK was observed in 71.4% (10/14) of ICC cases as compared with surrounding nontumour tissue. Likewise, expression of JDP, a downstream effector of the MAPK signalling, was scored as high intensity in 64.3% (9/14). Strikingly, elevated expression of JDP transcripts was also observed in two independent cohorts of human ICC (n = 149 and n = 109 per group, respectively) compared to surrounding normal liver tissue. Consistent with the in-vivo analyses of human samples, immunoblotting analyses showed constitutive activation of MAPK and expression of JDP in ICC-derived cells (i.e. SG231, CCLP-1 and HuCCT1). Using loss-of-function analyses, we demonstrates that knockdown of JDP in ICC-derived cells resulted in cell cycle arrest and reduced expression of cell cycle regulators (i.e. cyclins), and had minimal effect on apoptosis. Chemical inhibition of JDP significantly sensitises ICC-derived cells to cisplatinum (P < 0.001). Conclusion: These results demonstrate that enhanced activation of MAPK signalling is important for ICC cell proliferation and suggest that targeting its downstream effectors is a potential therapeutic strategy for ICC

Superplastic deformation in two microduplex stainless steels

The deformation behavior and mechanisms of superplastic flow in two microduplex stainless steels (SuperDux64 and Nitronic 19D) were studied at {similar_to}0.7T{sub m}. The two steels differed in initial grain size by a factor of 3. Both steels exhibited solute-drag-controlled grain boundary sliding in a high temperature {gamma}+{delta} phase field. In a lower temperature {gamma}+{sigma} phase field, the fine-grained steel ({bar L}=5{mu}m) exhibited climb-controlled grain boundary sliding and the coarser- grained steel ({bar L}=15{mu}m) exhibited solute-drag-controlled slip creep

Creep fracture during solute-drag creep and superplastic deformation

Creep fracture behavior has been studied in Al-Mg and Al-Mg-Mn alloys undergoing solute-drag creep and in microduplex stainless steel undergoing both solute-drag creep and superplastic deformation. Failure in these materials is found to be controlled by two mechanisms, neck formation and cavitation. The mechanism of creep fracture during solute-drag creep in Al-Mg is found to change from necking-controlled fracture to cavitation-controlled fracture as Mn content is increased. Binary Al-Mg material fails by neck formation during solute-drag creep, and cavities are formed primarily in the neck region due to high hydrostatic stresses. Ternary alloys of Al-Mg- Mn containing 0.25 and 0.50 wt % Mn exhibit more uniform cavitation, with the 0.50 Mn alloy clearly failing by cavity interlinkage. Failure in the microduplex stainless steel is dominated by neck formation during solute-drag creep deformation but is controlled by cavity growth and interlinkage during superplastic deformation. Cavitation was measured at several strains, and found to increase as an exponential function of strain. An important aspect of cavity growth in the stainless steel is the long latency time before significant cavitation occurs. For a short latency period, cavitation acts to significantly reduce ductility below that allowed by neck growth alone. This effect is most pronounced in materials with a high strain-rate sensitivity, for which neck growth occurs very slowly

Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis

OBJECTIVE: Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. DESIGN: Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice. RESULTS: We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes. CONCLUSIONS: These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH

Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (gt;99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMOdependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness