Inhibition of p38 pathway leads to OA-like changes in a rat animal model

Objectives The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is involved in a variety of inflammatory responses, including cytokine generation, cell differentiation proliferation and apoptosis. Here, we examined the effects of systemic p38 MAPK inhibition on cartilage cells and osteoarthritis (OA) disease progression by both in vitro and in vivo approaches. Methods p38 kinase activity was evaluated in normal and OA cartilage cells by measuring the amount of phosphorylated protein. To examine the function of p38 signaling pathway in vitro, normal chondrocytes were isolated and differentiated in the presence or absence of p38 inhibitor; SB203580 and analysed for chondrogenic phenotype. Effect of systemic p38 MAPK inhibition in normal and OA (induced by menisectomy) rats were analysed by treating animals with vehicle alone (DMS0) or p38 inhibitor (SB203580). Damage to the femur and tibial plateau was evaluated by modified Mankin score, histology and immunohistochemistry. Results Our in vitro studies have revealed that a down-regulation of chondrogenic and increase of hypertrophic gene expression occurs in the normal chondrocytes, when p38 is neutralized by a pharmacological inhibitor. We further observed that the basal levels of p38 phosphorylation were decreased in OA chondrocytes compared with normal chondrocytes. These findings together indicate the importance of this pathway in the regulation of cartilage physiology and its relevance to OA pathogenesis. At in vivo level, systematic administration of a specific p38 MAPK inhibitor, SB203580, continuously for over a month led to a significant loss of proteoglycan; aggrecan and cartilage thickness. On the other hand, SB203580 treated normal rats showed a significant increase in TUNEL positive cells, cartilage hypertrophy markers such as Type 10 collagen, Runt-related transcription factor and Matrix metalloproteinase-13 and substantially induced OA like phenotypic changes in the normal rats. In addition, menisectomy induced OA rat models that were treated with p38 inhibitor showed aggravation of cartilage damage. Conclusions In summary, this study has provided evidence that the component of the p38 MAPK pathway is important to maintain the cartilage health and its inhibition can lead to severe cartilage degenerative changes. The observations in this study highlight the possibility of using activators of the p38 pathway as an alternative approach in the treatment of OA.

‘Wanna do more math’: engaging underachieving Indigenous learners the YuMi Deadly way.

The Accelerating Indigenous Mathematics (AIM) Program offered by the YuMi Deadly Centre from QUT accelerates the mathematics learning of underperforming students in Years 8 - 10 by a) apportioning Years 2-10 Australian Curriculum: Mathematics content into three years, and b) provides a teaching approach that accelerates the mathematical learning. The philosophy of the YuMi Deadly teaching approach for mathematics is one that requires a ‘body’, ‘hand’, ‘mind’ pedagogy. This presentation will provide examples of the “‘body’, ‘hand’, ‘mind’” mathematics pedagogy. In AIM classrooms, mathematics is presented this approach is having a positive impact. Students are willing ‘to have a go’ without shame; and they develop the desire to learn and improve their numeracy.

Quantitative electroencephalographic comodulation : an investigation of patterns in chronic fatigue syndrome

Introduction. This is a pilot study of quantitative electro-encephalographic (QEEG) comodulation analysis, which is used to assist in identifying regional brain differences in those people suffering from chronic fatigue syndrome (CFS) compared to a normative database. The QEEG comodulation analysis examines spatial-temporal cross-correlation of spectral estimates in the resting dominant frequency band. A pattern shown by Sterman and Kaiser (2001) and referred to as the anterior posterior dissociation (APD) discloses a significant reduction in shared functional modulation between frontal and centro-parietal areas of the cortex. This research attempts to examine whether this pattern is evident in CFS. Method. Eleven adult participants, diagnosed by a physician as having CFS, were involved in QEEG data collection. Nineteen-channel cap recordings were made in five conditions: eyes-closed baseline, eyes-open, reading task one, math computations task two, and a second eyes-closed baseline. Results. Four of the 11 participants showed an anterior posterior dissociation pattern for the eyes-closed resting dominant frequency. However, seven of the 11 participants did not show this pattern. Examination of the mean 8-12 Hz amplitudes across three cortical regions (frontal, central and parietal) indicated a trend of higher overall alpha levels in the parietal region in CFS patients who showed the APD pattern compared to those who did not have this pattern. All patients showing the pattern were free of medication, while 71% of those absent of the pattern were using antidepressant medications. Conclusions. Although the sample is small, it is suggested that this method of evaluating the disorder holds promise. The fact that this pattern was not consistently represented in the CFS sample could be explained by the possibility of subtypes of CFS, or perhaps co-morbid conditions. Further, the use of antidepressant medications may mask the pattern by altering the temporal characteristics of the EEG. The results of this pilot study indicate that further research is warranted to verify that the pattern holds across the wider population of CFS sufferers.

Virtual design process : design validation tool schematic approach in car carrier

An important aspect of designing any product is validation. Virtual design process (VDP) is an alternative to hardware prototyping in which analysis of designs can be done without manufacturing physical samples. In recent years, VDP have been generated either for animation or filming applications. This paper proposes a virtual reality design process model on one of the applications when used as a validation tool. This technique is used to generate a complete design guideline and validation tool of product design. To support the design process of a product, a virtual environment and VDP method were developed that supports validation and an initial design cycle performed by a designer. The product model car carrier is used as illustration for which virtual design was generated. The loading and unloading sequence of the model for the prototype was generated using automated reasoning techniques and was completed by interactively animating the product in the virtual environment before complete design was built. By using the VDP process critical issues like loading, unloading, Australian Design rules (ADR) and clearance analysis were done. The process would save time, money in physical sampling and to large extent in complete math generation. Since only schematic models are required, it saves time in math modelling and handling of bigger size assemblies due to complexity of the models. This extension of VDP process for design evaluation is unique and was developed, implemented successfully. In this paper a Toll logistics and J Smith and Sons car carrier which is developed under author’s responsibility has been used to illustrate our approach of generating design validation via VDP.

Report on Innovation Working Group : The Mathematics Education into the 21st Century Project. Dresden, Saxony

This document reports on the Innovations Working Group that met at the 10th International Conference “Models in Developing Mathematics Education” from the 11-17th September 2009 in Dresden, Saxony. It briefly describes the over arching and consistent themes that emerged from the numerous papers presented. The authors and titles of each of the papers presented will be listed in Table 2.

Mandates: An Australian example at the Queensland University of Technology

This presentation describes a situation where an open access mandate was developed and implemented at an institutional level, in this case, an Australian University. Some conclusions are drawn about its effect over a five year period of implementation.

Leading learning within a PLC : implementing new mathematics content

This paper does two things. Firstly, it examines the literature that coalesces around theoretical models of teacher professional development (PD) within a professional learning community (PLC). Secondly, these models are used to analyse support provided to two year 3 teachers, while implementing the draft Queensland mathematics syllabus. The findings from this study suggest that the development of this small PLC extended the teachers’ Zone of Enactment which in turn led to teacher action and reflection. This was demonstrated by the teachers leading their own learning as well as that of their students.

Identifying the learning development of students who are refugees

Students who are refugees need understanding and support to settle successfully into mainstream Australian classrooms. Teachers not aware of students’ prior learning and the process of second language acquisition may have difficulty providing the most appropriate learning environments to meet these students’ needs. This study found that, with no coordination of information on students’ learning backgrounds nor of their learning needs and development, students were in danger of being identified as at-risk of having a learning disability, with little support to substantiate such claims.

Trailblazers

A recent study in the United Kingdom (Ofsted Report 2008) provides strong evidence that well-organized activities outside the classroom contribute significantly to the quality and depth of children's learning, including their personal, social, and emotional development. Outdoor math trails supply further evidence of such enhanced learning: They are meaningful, stimulating, challenging, and exciting for children. Most important, these trails invite all students, irrespective of their classroom achievement level, to participate successfully in the problem activities and gain a sense of pride in the mathematics they create. Additionally, Math trails empower lifelong learning. Integrating "outside" mathematics with "inside" classroom mathematics can sow the seeds to develop flexible, creative, future-oriented mathematical thinkers and problem solvers. Here, English et al discuss how to design and implement math trails to promote active, meaningful, real-world mathematical learning beyond the classroom walls.

Osteoarthritis Index delivered by mobile phone (m-WOMAC) is valid, reliable, and responsive

Objectives: To evaluate the validity, reliability and responsiveness of EDC using the WOMAC® NRS 3.1 Index on Motorola V3 mobile phones. ---------- Methods: Patients with osteoarthritis (OA) undergoing primary unilateral hip or knee joint replacement surgery were assessed pre-operatively and 3-4 months post-operatively. Patients completed the WOMAC® Index in paper (p-WOMAC®) and electronic (m-WOMAC®) format in random order. ---------- Results: 24 men and 38 women with hip and knee OA participated and successfully completed the m-WOMAC® questionnaire. Pearson correlations between the summated total index scores for the p-WOMAC® and m-WOMAC® pre- and post-surgery were 0.98 and 0.99 (p<0.0001). There was no clinically important or statistically significant between-method difference in the adjusted total summated scores, pre- and post-surgery (adjusted mean difference = 4.44, p = 0.474 and 1.73, p = 0.781). Internal consistency estimates of m-WOMAC® reliability were 0.87 – 0.98. The m-WOMAC® detected clinically important, statistically significant (p<0.0001) improvements in pain, stiffness, function and total index score. ---------- Conclusions: Sixty-two patients with hip and knee OA successfully completed EDC by Motorola V3 mobile phone using the m-WOMAC® NRS3.1 Index; completion times averaging only 1-1.5 minutes longer than the p-WOMAC® Index. Data were successfully and securely transmitted from patients in Australia to a server in the USA. There was close agreement and no significant differences between m-WOMAC® and p-WOMAC® scores. This study confirms the validity, reliability and responsiveness of the Exco InTouch engineered, Java-based m-WOMAC® Index application. EDC with the m-WOMAC® Index provides unique opportunities for using quantitative measurement in clinical research and practice.

In vitro cultivation of adult human chondrocytes : importance of culture system, oxygen and zonal differences

Articular cartilage exhibits limited intrinsic regenerative capacity and focal tissue defects can lead to the development of osteoarthritis (OA), a painful and debilitating loss of cartilage tissue. In Australia, 1.4 million people are affected by OA and its prevalence is increasing in line with current demographics. As treatment options are limited, new therapeutic approaches are being investigated including biological resurfacing of joints with tissue-engineered cartilage. Despite some progress in the field, major challenges remain to be addressed for large scale clinical success. For example, large numbers of chondrogenic cells are required for cartilage formation, but chondrocytes lose their chondrogenic phenotype (dedifferentiate) during in vitro propagation. Additionally, the zonal organization of articular cartilage is critical for normal cartilage function, but development of zonal structure has been largely neglected in cartilage repair strategies. Therefore, we hypothesised that culture conditions for freshly isolated human articular chondrocytes from non-OA and OA sources can be improved by employing microcarrier cultures and a reduced oxygen environment and that oxygen is a critical factor in the maintenance of the zonal chondrocyte phenotype. Microcarriers have successfully been used to cultivate bovine chondrocytes, and offer a potential alternative for clinical expansion of human chondrocytes. We hypothesised that improved yields can be achieved by propagating human chondrocytes on microcarriers. We found that cells on microcarriers acquired a flattened, polygonal morphology and initially proliferated faster than monolayercultivated cells. However, microcarrier cultivation over four weeks did not improve growth rates or the chondrogenic potential of non-OA and OA human articular chondrocytes over conventional monolayer cultivation. Based on these observations, we aimed to optimise culture conditions by modifying oxygen tension, to more closely reflect the in vivo environment. We found that propagation at 5% oxygen tension (moderate hypoxia) did not improve proliferation or redifferentiation capacity of human osteoarthritic chondrocytes. Moderate hypoxia increased the expression of chondrogenic markers during redifferentiation. However, osteoarthritic chondrocytes cultivated on microcarriers exhibited lower expression levels of chondrogenic surface marker proteins and had at best equivalent redifferentiation capacities compared to monolayer-cultured cells. This suggests that monolayer culture with multiple passaging potentially selects for a subpopulation of cells with higher differentiation capacity, which are otherwise rare in osteoarthritic, aged cartilage. However, fibroblastic proteins were found to be highly expressed in all cultures of human osteoarthritic chondrocytes indicating the presence of a high proportion of dedifferentiated, senescent cells with a chondrocytic phenotype that was not rescued by moderate hypoxia. The different zones of cartilage support chondrocyte subpopulations, which exhibit characteristic protein expression and experience varying oxygen tensions. We, therefore, hypothesised that oxygen tension affects the zonal marker expression of human articular chondrocytes isolated from the different cartilage layers. We found that zonal chondrocytes maintained these phenotypic differences during in vitro cultivation. Low oxygen environments favoured the expression of the zonal marker proteoglycan 4 in superficial cells, most likely through the promotion of chondrogenesis. The putative zonal markers clusterin and cartilage intermediate layer protein were found to be expressed by all subpopulations of human osteoarthritic chondrocytes ex vivo and, thus, may not be reliable predictors of in vitro stratification using these clinically relevant cells. The findings in this thesis underline the importance of considering low oxygen conditions and zonal stratification when creating native-like cartilaginous constructs. We have not yet found the right cues to successfully cultivate clinically-relevant human osteoarthritic chondrocytes in vitro. A more thorough understanding of chondrocyte biology and the processes of chondrogenesis are required to ensure the clinical success of cartilage tissue engineering.

ERK-1/2 and p38 in the Regulation of Hypertrophic Changes of Normal Articular Cartilage Chondrocytes Induced by Osteoarthritic Subchondral Osteoblasts

Objective. Previous studies have shown the influence of subchondral bone osteoblasts (SBOs) on phenotypical changes of articular cartilage chondrocytes (ACCs) during the development of osteoarthritis (OA). The molecular mechanisms involved during this process remain elusive, in particular, the signal transduction pathways. The aim of this study was to investigate the in vitro effects of OA SBOs on the phenotypical changes in normal ACCs and to unveil the potential involvement of MAPK signaling pathways during this process. Methods. Normal and arthritic cartilage and bone samples were collected for isolation of ACCs and SBOs. Direct and indirect coculture models were applied to study chondrocyte hypertrophy under the influence of OA SBOs. MAPKs in the regulation of the cell–cell interactions were monitored by phosphorylated antibodies and relevant inhibitors. Results. OA SBOs led to increased hypertrophic gene expression and matrix calcification in ACCs by means of both direct and indirect cell–cell interactions. In this study, we demonstrated for the first time that OA SBOs suppressed p38 phosphorylation and induced ERK-1/2 signal phosphorylation in cocultured ACCs. The ERK-1/2 pathway inhibitor PD98059 significantly attenuated the hypertrophic changes induced by conditioned medium from OA SBOs, and the p38 inhibitor SB203580 resulted in the up-regulation of hypertrophic genes in ACCs. Conclusion. The findings of this study suggest that the pathologic interaction of OA SBOs and ACCs is mediated via the activation of ERK-1/2 phosphorylation and deactivation of p38 phosphorylation, resulting in hypertrophic differentiation of ACCs.

The Queensland Cancer Physics Collaborative and the Quantitative Biomedical Imaging & Characterisation (Q-BIC) Research Group

a presentation about immersive visualised simulation systems, image analysis and GPGPU Techonology

Sensitivity of the lane change test as a measure of in-vehicle system demand

The Lane Change Test (LCT) is one of the growing number of methods developed to quantify driving performance degradation brought about by the use of in-vehicle devices. Beyond its validity and reliability, for such a test to be of practical use, it must also be sensitive to the varied demands of individual tasks. The current study evaluated the ability of several recent LCT lateral control and event detection parameters to discriminate between visual-manual and cognitive surrogate In-Vehicle Information System tasks with different levels of demand. Twenty-seven participants (mean age 24.4 years) completed a PC version of the LCT while performing visual search and math problem solving tasks. A number of the lateral control metrics were found to be sensitive to task differences, but the event detection metrics were less able to discriminate between tasks. The mean deviation and lane excursion measures were able to distinguish between the visual and cognitive tasks, but were less sensitive to the different levels of task demand. The other LCT metrics examined were less sensitive to task differences. A major factor influencing the sensitivity of at least some of the LCT metrics could be the type of lane change instructions given to participants. The provision of clear and explicit lane change instructions and further refinement of its metrics will be essential for increasing the utility of the LCT as an evaluation tool.