Endophenotype profiles of MTHFR and ACE gene polymorphisms in migraine susceptibility

Background Migraine is a debilitating neurological disorder affecting approximately 12% of the Caucasian population. There are two main sub-types of migraine, migraine without aura (MO) and migraine with aura (MA). Migraine exhibits varied phenotypic expression with sufferers experiencing a range of neurological and other symptoms. It is likely that multiple susceptibility genes play a role in this varied phenotypic expression, thus investigation of genotype-phenotype relationships may provide valuable insights into the role of susceptibility genes in this disorder. Methods This study investigated the links between migraine susceptibility genes, methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE), and clinical manifestation through statistical analyses. Results The result showed that for the MTHFR genotypes, there was a statistically significant correlation with the TT homozygous genotype and visual disturbances, unilateral head pain and physical activity discomforts. It was also found that bilateral head pain was associated with the male gender. Conclusion From these study results, it is plausible to state that MTHFR genotypes affect the phenotypic expression of migraine disease manifestation.

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10-45), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10-7). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

Building project competence : developing dynamic capabilities with knowledge governance mechanisms

This research investigates the development of project competence, and particularly, three related dynamic capabilities (shifting, adapting, leveraging) that contribute to project competence development. In doing so, we make use of the emerging literature on knowledge governance and theorize how knowledge governance mechanisms can move the organization towards desired knowledge-based goals. A multiple-case study comprising 23 cases advances our understanding of the elements that trigger, enable, hamper, and drive shifting, leveraging and adapting. Finally, the paper offers a tentative framework of dynamic capability building promoting project competence development.

Metastability and emergent performance of dynamic interceptive actions

Objectives: Adaptive patterning of human movement is context specific and dependent on interacting constraints of the performer–environment relationship. Flexibility of skilled behaviour is predicated on the capacity of performers to move between different states of movement organisation to satisfy dynamic task constraints, previously demonstrated in studies of visual perception, bimanual coordination, and an interceptive combat task. Metastability is a movement system property that helps performers to remain in a state of relative coordination with their performance environments, poised between multiple co-existing states (stable and distinct movement patterns or responses). The aim of this study was to examine whether metastability could be exploited in externally paced interceptive actions in fast ball sports, such as cricket. Design: Here we report data on metastability in performance of multi-articular hitting actions by skilled junior cricket batters (n = 5). Methods: Participants’ batting actions (key movement timings and performance outcomes) were analysed in four distinct performance regions varied by ball pitching (bounce) location. Results: Results demonstrated that, at a pre-determined distance to the ball, participants were forced into a meta-stable region of performance where rich and varied patterns of functional movement behaviours emerged. Participants adapted the organisation of responses, resulting in higher levels of variability in movement timing in this performance region, without detrimental effects on the quality of interceptive performance outcomes. Conclusions: Findings provide evidence for the emergence of metastability in a dynamic interceptive action in cricket batting. Flexibility and diversity of movement responses were optimised using experiential knowledge and careful manipulation of key task constraints of the specific sport context.

Traits of fear resistance and susceptibility in an advanced intercross line

Genetic variability in the strength and precision of fear memory is hypothesised to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalised fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic-pituitary-adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimise false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology. Through short-term selection in a B6D2 advanced intercross line we created mouse populations divergent for the retention of Pavlovian fear memory. Trait distinctions in HPA-axis drive and fear network circuitry could be made between naïve animals in the two lines. These data demonstrate underlying physiological and neurological differences between Fear-Susceptible and Fear-Resistant animals in a natural population. F-S and F-R mice may therefore be relevant to a spectrum of disorders including depression, anxiety disorders and PTSD for which altered fear processing occurs.

Dynamic weaving in aspect oriented business process management

Reducing complexity in Information Systems is an important topic in both research and industry. One strategy to deal with complexity is separation of concerns, which results in less complex, easily maintainable and more reusable systems. Separation of concerns can be addressed through the Aspect Oriented paradigm. Although this paradigm has been well researched in programming, it is still at the preliminary stage in the area of Business Process Management. While some efforts have been made to extend business process modelling with aspect oriented capability, it has not yet been investigated how aspect oriented business process models should be executed at runtime. In this paper, we propose a generic solution to support execution of aspect oriented business process models based on the principle behind dynamic weaving of aspects. This solution is formally specified using Coloured Petri Nets. The resulting formal specification serves as the blueprint to the implementation of a service module in the framework of a state-of-the-art Business Process Management System. Using this developed artefact, a case study is performed in which two simplified processes from real business in the domain of banking are modelled and executed in an aspect oriented manner. Through this case study, we also demonstrate that adoption of aspect oriented modularization increases the reusability while reducing the complexity of business process models in practice.

Dynamic load-sharing of longitudinal-connected air suspensions of a tri-axle semi-trailer

The effects of suspension parameters and driving conditions on dynamic load-sharing of longitudinal-connected air suspensions of a tri-axle semi-trailer are investigated in this study. A novel nonlinear model of a multi-axle semi-trailer with longitudinal-connected air suspensions is formulated based on fluid mechanics and thermodynamics and validated through test results. The effects of road surface conditions, driving speeds, air line inside diameter and connector inside diameter on dynamic load-sharing capability of the semi-trailer were analyzed in terms of load-sharing criteria. Simulation results indicate that, when larger air lines and connectors are employed, the DLSC (Dynamic Load-Sharing Coefficient) optimization ratio reaches its peak value when the road roughness is medium. The optimization ratio fluctuates in a complex manner as driving speed increases. The results also indicate that if the air line inside diameter is always assumed to be larger than the connector inside diameter, the influence of air line inside diameter on load-sharing is more significant than that of the connector inside diameter. The proposed approach can be used for further study of the influence of additional factors (such as vehicle load, static absolute air pressure and static height of air spring) on load-sharing and the control methods for multi-axle air suspensions with longitudinal air line.

A framework of Dynamic Difficulty Adjustment in competitive multiplayer video games

The balance between player competence and the challenge presented by a task has been acknowledged as a major factor in providing optimal experience in video games. While Dynamic Difficulty Adjustment (DDA) presents methods for adjusting difficulty in real-time during singleplayer games, little research has explored its application in competitive multiplayer games where challenge is dictated by the competence of human opponents. By conducting a formal review of 180 existing competitive multiplayer games, it was found that a large number of modern games are utilizing DDA techniques to balance challenge between human opponents. From this data, we propose a preliminary framework for classifying Multiplayer Dynamic Difficulty Adjustment (mDDA) instances.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Computational fluid dynamic analysis of intracranial aneurysmal bleb formation

Background The management of unruptured aneurysms is controversial with the decision to treat influenced by aneurysm characteristics including size and morphology. Aneurysmal bleb formation is thought to be associated with an increased risk of rupture. Objective To correlate computational fluid dynamic (CFD) indices with bleb formation. Methods Anatomical models were constructed from three-dimensional rotational angiogram (3DRA) data in 27 patients with cerebral aneurysms harbouring single blebs. Additional models representing the aneurysm before bleb formation were constructed by digitally removing the bleb. We characterised haemodynamic features of models both with and without the bleb using CFDs. Flow structure, wall shear stress (WSS), pressure and oscillatory shear index (OSI) were analysed. Results There was a statistically significant association between bleb location at or adjacent to the point of maximal WSS (74.1%, p=0.019), irrespective of rupture status. Aneurysmal blebs were related to the inflow or outflow jet in 88.9% of cases (p<0.001) whilst 11.1% were unrelated. Maximal wall pressure and OSI were not significantly related to bleb location. The bleb region attained a lower WSS following its formation in 96.3% of cases (p<0.001) and was also lower than the average aneurysm WSS in 86% of cases (p<0.001). Conclusion Cerebral aneurysm blebs generally form at or adjacent to the point of maximal WSS and are aligned with major flow structures. Wall pressure and OSI do not contribute to determining bleb location. The measurement of WSS using CFD models may potentially predict bleb formation and thus improve the assessment of rupture risk in unruptured aneurysms.

Experiential knowledge of expert coaches can help identify informational constraints on performance of dynamic interceptive actions

Coordination of dynamic interceptive movements is predicated on cyclical relations between an individual's actions and information sources from the performance environment. To identify dynamic informational constraints, which are interwoven with individual and task constraints, coaches’ experiential knowledge provides a complementary source to support empirical understanding of performance in sport. In this study, 15 expert coaches from 3 sports (track and field, gymnastics and cricket) participated in a semi-structured interview process to identify potential informational constraints which they perceived to regulate action during run-up performance. Expert coaches’ experiential knowledge revealed multiple information sources which may constrain performance adaptations in such locomotor pointing tasks. In addition to the locomotor pointing target, coaches’ knowledge highlighted two other key informational constraints: vertical reference points located near the locomotor pointing target and a check mark located prior to the locomotor pointing target. This study highlights opportunities for broadening the understanding of perception and action coupling processes, and the identified information sources warrant further empirical investigation as potential constraints on athletic performance. Integration of experiential knowledge of expert coaches with theoretically driven empirical knowledge represents a promising avenue to drive future applied science research and pedagogical practice.

Dynamic load sharing in heavy vehicle suspensions - further analysis of the equalisation effects of larger air lines

This paper provides details on comparative testing of axle-to-chassis forces of two heavy vehicles (HVs) based on an experimental programme carried out in 2007. Dynamic forces at the air springs were measured against speed and roughness values for the test roads used. One goal of that programme was to determine whether dynamic axle-to-chassis forces could be reduced by using larger-than-standard diameter longitudinal air lines. This paper presents a portion of the methodology, analysis and results from that programme. Two analytical techniques and their results are presented. The first uses correlation coefficients of the forces between air springs and the second is a student’s t-test. These were used to determine the causality surrounding improved dynamic load sharing between heavy vehicle air springs with larger air lines installed longitudinally compared with the standard sized air lines installed on the majority of air-sprung heavy vehicles.

Biomechanical characteristics of peripheral diabetic neuropathy : a systematic review and meta-analysis of findings from the gait cycle, muscle activity and dynamic barefoot plantar pressure

Background: Diabetic peripheral neuropathy is an important cause of foot ulceration and limb loss. This systematic review and meta-analysis investigated the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and dynamic plantar pressures. Methods: Electronic databases were searched systematically for articles reporting the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and plantar pressures. Searches were restricted to articles published between January 2000 and April 2012. Outcome measures assessed included spatiotemporal parameters, lower limb kinematics, kinetics, muscle activation and plantar pressure. Meta-analyses were carried out on all outcome measures reported by ≥3 studies. Findings: Sixteen studies were included consisting of 382 neuropathy participants, 216 diabetes controls without neuropathy and 207 healthy controls. Meta-analysis was performed on 11 gait variables. A high level of heterogeneity was noted between studies. Meta-analysis results suggested a longer stance time and moderately higher plantar pressures in diabetic peripheral neuropathy patients at the rearfoot, midfoot and forefoot compared to controls. Systematic review of studies suggested potential differences in the biomechanical characteristics (kinematics, kinetics, EMG) of diabetic neuropathy patients. However these findings were inconsistent and limited by small sample sizes.; Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies. Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies.

Dynamic effects of electrical pitting in steam-turbine tilting-pad thrust-bearings

This paper merges the analysis of a case history and the simplified theoretical model related to a rather singular phenomenon that may happen in rotating machinery. Starting from the first, a small industrial steam turbine experienced a very strange behavior during megawatt load. When the unit was approaching the maximum allowed power, the temperature of the babbitt metal of the pads of the thrust bearing showed constant increase with an unrecoverable drift. Bearing inspection showed that pad trailing edge had the typical aspect of electrical pitting. This kind of damage was not reparable and bearing pads had to replaced. This problem occurred several times in sequence and was solved only by adding further ground brushes to the shaft-line. Failure analysis indicated electrodischarge machining as the root fault. A specific model, able to take into consideration the effect of electrical pitting and loading capacity decreasing as a consequence of the damage of the babbitt metal, is proposed in the paper and shows that the phenomenon causes the irretrievable failure of the thrust bearing.

FRC erection stages dynamic behaviour under wind loads

Buffeting response of a cable-stayed bridge under construction is investigated through wind tunnel tests and numerical simulations. Two configurations of the erection stage have been considered and compared in terms of dynamic response and internal forces using the results of the experimental aeroelastic models. Moreover the results of a numerical model able to simulate the simultaneous effects of vortex shedding from tower and aeroelastic response of the deck are compared to the wind tunnel ones.