Reduced variance in monozygous twins for multiple MR parameters : implications for disease studies and the genetic basis of brain structure

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest. Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation. Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA). This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

The role of the multiple banded antigen of ureaplasma parvum in intra-amniotic infection : major virulence factor or decoy?

The multiple banded antigen (MBA) is a predicted virulence factor of Ureaplasma species. Antigenic variation of the MBA is a potential mechanism by which ureaplasmas avoid immune recognition and cause chronic infections of the upper genital tract of pregnant women. We tested whether the MBA is involved in the pathogenesis of intra-amniotic infection and chorioamnionitis by injecting virulent or avirulent-derived ureaplasma clones (expressing single MBA variants) into the amniotic fluid of pregnant sheep. At 55 days of gestation pregnant ewes (n = 20) received intra-amniotic injections of virulent-derived or avirulent-derived U. parvum serovar 6 strains (2×104 CFU), or 10B medium (n = 5). Amniotic fluid was collected every two weeks post-infection and fetal tissues were collected at the time of surgical delivery of the fetus (140 days of gestation). Whilst chronic colonisation was established in the amniotic fluid of animals infected with avirulent-derived and virulent-derived ureaplasmas, the severity of chorioamnionitis and fetal inflammation was not different between these groups (p>0.05). MBA size variants (32–170 kDa) were generated in vivo in amniotic fluid samples from both the avirulent and virulent groups, whereas in vitro antibody selection experiments led to the emergence of MBA-negative escape variants in both strains. Anti-ureaplasma IgG antibodies were detected in the maternal serum of animals from the avirulent (40%) and virulent (55%) groups, and these antibodies correlated with increased IL-1β, IL-6 and IL-8 expression in chorioamnion tissue (p<0.05). We demonstrate that ureaplasmas are capable of MBA phase variation in vitro; however, ureaplasmas undergo MBA size variation in vivo, to potentially prevent eradication by the immune response. Size variation of the MBA did not correlate with the severity of chorioamnionitis. Nonetheless, the correlation between a maternal humoral response and the expression of chorioamnion cytokines is a novel finding. This host response may be important in the pathogenesis of inflammation-mediated adverse pregnancy outcomes.

Age-related loss of brain volume and T2 relaxation time in youth with type 1 diabetes

OBJECTIVE: Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain. RESEARCH DESIGN AND METHODS: Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient. RESULTS: Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time. CONCLUSIONS: We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified.

A longitudinal assessment of chronic wound fluid to detect biochemical indicators of healing

Chronic venous leg ulcers are a detrimental health issue plaguing our society, resulting in long term pain, immobility and decreased quality of life for a large proportion of sufferers. The frequency of these chronic wounds has led current research to focus on the wound environment to provide important information regarding the prolonged, fluctuated or static healing patterns of these wounds. Disruption to the normal wound healing process results in release of multiple factors in the wound environment that could correlate to wound chronicity. These biochemical factors can often be detected through non-invasively sampling chronic wound fluid (CWF) from the site of injury. Of note, whilst there are numerous studies comparing acute and chronic wound fluids, there have not been any reports in the literature employing a longitudinal study in order to track biochemical changes in wound fluid as patients transition from a non-healing to healed state. Initially the objective of this study was to identify biochemical changes in CWF associated with wound healing using a proteomic approach. The proteomic approach incorporated a multi-dimensional liquid chromatography fractionation technique coupled with mass spectrometry (MS) to enable identification of proteins present in lower concentrations in CWF. Not surprisingly, many of the proteins identified in wound fluid were acute phase proteins normally expressed during the inflammatory phase of healing. However, the number of proteins positively identified by MS was quite low. This was attributed to the diverse range in concentration of protein species in CWF making it challenging to detect the diagnostically relevant low molecular weight proteins. In view of this, SELDI-TOF MS was also explored as a means to target low molecular weight proteins in sequential patient CWF samples during the course of healing. Unfortunately, the results generated did not yield any peaks of interest that were altered as wounds transitioned to a healed state. During the course of proteomic assessment of CWF, it became evident that a fraction of non-proteinaceous compounds strongly absorbed at 280 nm. Subsequent analyses confirmed that most of these compounds were in fact part of the purine catabolic pathway, possessing distinctive aromatic rings and which results in high absorbance at 254 nm. The accumulation of these purinogenic compounds in CWF suggests that the wound bed is poorly oxygenated resulting in a switch to anaerobic metabolism and consequently ATP breakdown. In addition, the presence of the terminal purine catabolite, uric acid (UA), indicates that the enzyme xanthine oxidoreductase (XOR) catalyses the reaction of hypoxanthine to xanthine and finally to UA. More importantly, the studies provide evidence for the first time of the exogenous presence of XOR in CWF. XOR is the only enzyme in humans capable of catalysing the production of UA in conjunction with a burst of the highly reactive superoxide radical and other oxidants like H2O2. Excessive release of these free radicals in the wound environment can cause cellular damage disrupting the normal wound healing process. In view of this, a sensitive and specific assay was established for monitoring low concentrations of these catabolites in CWF. This procedure involved combining high performance liquid chromatography (HPLC) with tandem mass spectrometry and multiple reaction monitoring (MRM). This application was selective, using specific MRM transitions and HPLC separations for each analyte, making it ideal for the detection and quantitation of purine catabolites in CWF. The results demonstrated that elevated levels of UA were detected in wound fluid obtained from patients with clinically worse ulcers. This suggests that XOR is active in the wound site generating significant amounts of reactive oxygen species (ROS). In addition, analysis of the amount of purine precursors in wound fluid revealed elevated levels of purine precursors in wound fluid from patients with less severe ulcers. Taken together, the results generated in this thesis suggest that monitoring changes of purine catabolites in CWF is likely to provide valuable information regarding the healing patterns of chronic venous leg ulcers. XOR catalysis of purine precursors not only provides a method for monitoring the onset, prognosis and progress of chronic venous leg ulcers, but also provides a potential therapeutic target by inhibiting XOR, thus blocking UA and ROS production. Targeting a combination of these purinogenic compounds and XOR could lead to the development of novel point of care diagnostic tests. Therefore, further investigation of these processes during wound healing will be worthwhile and may assist in elucidating the pathogenesis of this disease state, which in turn may lead to the development of new diagnostics and therapies that target these processes.

Handling incomplete data in survival analysis with multiple covariates

This paper studies the missing covariate problem which is often encountered in survival analysis. Three covariate imputation methods are employed in the study, and the effectiveness of each method is evaluated within the hazard prediction framework. Data from a typical engineering asset is used in the case study. Covariate values in some time steps are deliberately discarded to generate an incomplete covariate set. It is found that although the mean imputation method is simpler than others for solving missing covariate problems, the results calculated by it can differ largely from the real values of the missing covariates. This study also shows that in general, results obtained from the regression method are more accurate than those of the mean imputation method but at the cost of a higher computational expensive. Gaussian Mixture Model (GMM) method is found to be the most effective method within these three in terms of both computation efficiency and predication accuracy.

Optimal sitting and sizing of distributed generators considering plug-in electric vehicles

Some uncertainties such as the stochastic input/output power of a plug-in electric vehicle due to its stochastic charging and discharging schedule, that of a wind unit and that of a photovoltaic generation source, volatile fuel prices and future uncertain load growth, all together could lead to some risks in determining the optimal siting and sizing of distributed generators (DGs) in distributed systems. Given this background, under the chance constrained programming (CCP) framework, a new method is presented to handle these uncertainties in the optimal sitting and sizing problem of DGs. First, a mathematical model of CCP is developed with the minimization of DGs investment cost, operational cost and maintenance cost as well as the network loss cost as the objective, security limitations as constraints, the sitting and sizing of DGs as optimization variables. Then, a Monte Carolo simulation embedded genetic algorithm approach is developed to solve the developed CCP model. Finally, the IEEE 37-node test feeder is employed to verify the feasibility and effectiveness of the developed model and method. This work is supported by an Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) Project on Intelligent Grids Under the Energy Transformed Flagship, and Project from Jiangxi Power Company.

Some reflections about P2M : the place of the mirror

The purpose of this paper is to provide some insights about P2M, and more specifically, to develop some thoughts about Project Management seen as a Mirror, a place for reflection…, between the Mission of organisation and its actual creation of Values (with s: a source of value for people, organisations and society). This place is the realm of complexity, of interactions between multiple variables, each of them having a specific time horizon and occupying a specific place, playing a specific role. Before developing this paper I would like to borrow to my colleague and friend, Professor Ohara, the following, part of a paper going to be presented at IPMA World Congress, in New Delhi later this year in November 2005. “P2M is the Japanese version of project & program management, which is the first standard guide for education and certification developed in 2001. A specific finding of P2M is characterized by “mission driven management of projects” or a program which harness complexity of problem solving observed in the interface between technical system and business model.” (Ohara, 2005, IPMA Conference, New Delhi) “The term of “mission” is a key word in the field of corporate strategy, where it expresses raison d’être or “value of business”. It is more specifically used for expressing “the client needs” in terms of a strategic business unit. The concept of mission is deemed to be a useful tool to share essential content of value and needs in message for complex project.” (Ohara, 2005, IPMA Conference, New Delhi) “Mission is considered as a significant “metamodel representation” by several reasons. First, it represents multiple values for aspiration. The central objective of mission initiative is profiling of ideality in the future from reality, which all stakeholders are glad to accept and share. Second, it shall be within a stretch of efforts, and not beyond or outside of the realization. Though it looks like unique, it has to depict a solid foundation. The pragmatic sense of equilibrium between innovation and adaptation is required for the mission. Third, it shall imply a rough sketch for solution to critical issues for problems in reality.” (Ohara, 2005, IPMA Conference, New Delhi) “Project modeling” idea has been introduced in P2M program management. A package of three project models of “scheme”, “system” and “service” are given as a reference type program. (Ohara, 2005, IPMA Conference, New Delhi) If these quotes apply to P2M, they are fully congruent with the results of the research undertaken and the resulting meta-model & meta-method developed by the CIMAP, ESC Lille Research Centre in Project & Program Management, since the 80’s. The paper starts by questioning the common Project Management (PM) paradigm. Then discussing the concept of Project, it argues that an alternative epistemological position should be taken to capture Page 2 / 11 the very nature of the PM field. Based on this, a development about “the need of modelling to understand” is proposed grounded on two theoretical roots. This leads to the conclusion that, in order to enables this modelling, a standard approach is necessary, but should be understood under the perspective of the Theory of Convention in order to facilitate a situational and contextual application.

3D reconstruction of long bones utilising magnetic resonance imaging (MRI)

The design of pre-contoured fracture fixation implants (plates and nails) that correctly fit the anatomy of a patient utilises 3D models of long bones with accurate geometric representation. 3D data is usually available from computed tomography (CT) scans of human cadavers that generally represent the above 60 year old age group. Thus, despite the fact that half of the seriously injured population comes from the 30 year age group and below, virtually no data exists from these younger age groups to inform the design of implants that optimally fit patients from these groups. Hence, relevant bone data from these age groups is required. The current gold standard for acquiring such data–CT–involves ionising radiation and cannot be used to scan healthy human volunteers. Magnetic resonance imaging (MRI) has been shown to be a potential alternative in the previous studies conducted using small bones (tarsal bones) and parts of the long bones. However, in order to use MRI effectively for 3D reconstruction of human long bones, further validations using long bones and appropriate reference standards are required. Accurate reconstruction of 3D models from CT or MRI data sets requires an accurate image segmentation method. Currently available sophisticated segmentation methods involve complex programming and mathematics that researchers are not trained to perform. Therefore, an accurate but relatively simple segmentation method is required for segmentation of CT and MRI data. Furthermore, some of the limitations of 1.5T MRI such as very long scanning times and poor contrast in articular regions can potentially be reduced by using higher field 3T MRI imaging. However, a quantification of the signal to noise ratio (SNR) gain at the bone - soft tissue interface should be performed; this is not reported in the literature. As MRI scanning of long bones has very long scanning times, the acquired images are more prone to motion artefacts due to random movements of the subject‟s limbs. One of the artefacts observed is the step artefact that is believed to occur from the random movements of the volunteer during a scan. This needs to be corrected before the models can be used for implant design. As the first aim, this study investigated two segmentation methods: intensity thresholding and Canny edge detection as accurate but simple segmentation methods for segmentation of MRI and CT data. The second aim was to investigate the usability of MRI as a radiation free imaging alternative to CT for reconstruction of 3D models of long bones. The third aim was to use 3T MRI to improve the poor contrast in articular regions and long scanning times of current MRI. The fourth and final aim was to minimise the step artefact using 3D modelling techniques. The segmentation methods were investigated using CT scans of five ovine femora. The single level thresholding was performed using a visually selected threshold level to segment the complete femur. For multilevel thresholding, multiple threshold levels calculated from the threshold selection method were used for the proximal, diaphyseal and distal regions of the femur. Canny edge detection was used by delineating the outer and inner contour of 2D images and then combining them to generate the 3D model. Models generated from these methods were compared to the reference standard generated using the mechanical contact scans of the denuded bone. The second aim was achieved using CT and MRI scans of five ovine femora and segmenting them using the multilevel threshold method. A surface geometric comparison was conducted between CT based, MRI based and reference models. To quantitatively compare the 1.5T images to the 3T MRI images, the right lower limbs of five healthy volunteers were scanned using scanners from the same manufacturer. The images obtained using the identical protocols were compared by means of SNR and contrast to noise ratio (CNR) of muscle, bone marrow and bone. In order to correct the step artefact in the final 3D models, the step was simulated in five ovine femora scanned with a 3T MRI scanner. The step was corrected using the iterative closest point (ICP) algorithm based aligning method. The present study demonstrated that the multi-threshold approach in combination with the threshold selection method can generate 3D models from long bones with an average deviation of 0.18 mm. The same was 0.24 mm of the single threshold method. There was a significant statistical difference between the accuracy of models generated by the two methods. In comparison, the Canny edge detection method generated average deviation of 0.20 mm. MRI based models exhibited 0.23 mm average deviation in comparison to the 0.18 mm average deviation of CT based models. The differences were not statistically significant. 3T MRI improved the contrast in the bone–muscle interfaces of most anatomical regions of femora and tibiae, potentially improving the inaccuracies conferred by poor contrast of the articular regions. Using the robust ICP algorithm to align the 3D surfaces, the step artefact that occurred by the volunteer moving the leg was corrected, generating errors of 0.32 ± 0.02 mm when compared with the reference standard. The study concludes that magnetic resonance imaging, together with simple multilevel thresholding segmentation, is able to produce 3D models of long bones with accurate geometric representations. The method is, therefore, a potential alternative to the current gold standard CT imaging.

Information sharing in Onesocialweb using a multiple profile manager to better informed medical decision making processes

The study shows an alternative solution to existing efforts at solving the problem of how to centrally manage and synchronise users’ Multiple Profiles (MP) across multiple discrete social networks. Most social network users hold more than one social network account and utilise them in different ways depending on the digital context (Iannella, 2009a). They may, for example, enjoy friendly chat on Facebook1, professional discussion on LinkedIn2, and health information exchange on PatientsLikeMe3 In this thesis the researcher proposes a framework for the management of a user’s multiple online social network profiles. A demonstrator, called Multiple Profile Manager (MPM), will be showcased to illustrate how effective the framework will be. The MPM will achieve the required profile management and synchronisation using a free, open, decentralized social networking platform (OSW) that was proposed by the Vodafone Group in 2010. The proposed MPM will enable a user to create and manage an integrated profile (IP) and share/synchronise this profile with all their social networks. The necessary protocols to support the prototype are also proposed by the researcher. The MPM protocol specification defines an Extensible Messaging and Presence Protocol (XMPP) extension for sharing vCard and social network accounts information between the MPM Server, MPM Client, and social network sites (SNSs). . Therefore many web users need to manage disparate profiles across many distributed online sources. Maintaining these profiles is cumbersome, time-consuming, inefficient, and may lead to lost opportunity. The writer of this thesis adopted a research approach and a number of use cases for the implementation of the project. The use cases were created to capture the functional requirements of the MPM and to describe the interactions between users and the MPM. In the research a development process was followed in establishing the prototype and related protocols. The use cases were subsequently used to illustrate the prototype via the screenshots taken of the MPM client interfaces. The use cases also played a role in evaluating the outcomes of the research such as the framework, prototype, and the related protocols. An innovative application of this project is in the area of public health informatics. The researcher utilised the prototype to examine how the framework might benefit patients and physicians. The framework can greatly enhance health information management for patients and more importantly offer a more comprehensive personal health overview of patients to physicians. This will give a more complete picture of the patient’s background than is currently available and will prove helpful in providing the right treatment. The MPM prototype and related protocols have a high application value as they can be integrated into the real OSW platform and so serve users in the modern digital world. They also provide online users with a real platform for centrally storing their complete profile data, efficiently managing their personal information, and moreover, synchronising the overall complete profile with each of their discrete profiles stored in their different social network sites.

Challenges in the context-aware management of business processes : a multiple case study

Current conceptualizations of organizational processes consider them as internally optimized yet static systems. Still, turbulences in the contextual environment of a firm often lead to adaptation requirements that these processes are unable to fulfil. Based on a multiple case study of the core processes of two large organizations, we offer an extended conceptualisation of business processes as complex adaptive systems. This conceptualization can enable firms to optimise business processes by analysing operations in different contexts and by examining the complex interaction between external, contextual elements and internal agent schemata. From this analysis, we discuss how information technology can play a vital goal in achieving this goal by providing discovery, analysis, and automation support. We detail implications for research and practice.

The FAM deubiquitylating enzyme localizes to multiple points of protein trafficking in epithelia, where it associates with E-cadherin and β-catenin

Ubiquitylation is a necessary step in the endocytosis and lysosomal trafficking of many plasma membrane proteins and can also influence protein trafficking in the biosynthetic pathway. Although a molecular understanding of ubiquitylation in these processes is beginning to emerge, very little is known about the role deubiquitylation may play. Fat Facets in mouse (FAM) is substrate-specific deubiquitylating enzyme highly expressed in epithelia where it interacts with its substrate, β-catenin. Here we show, in the polarized intestinal epithelial cell line T84, FAM localized to multiple points of protein trafficking. FAM interacted with β-catenin and E-cadherin in T84 cells but only in subconfluent cultures. FAM extensively colocalized with β-catenin in cytoplasmic puncta but not at sites of cell-cell contact as well as immunoprecipitating with β-catenin and E-cadherin from a higher molecular weight complex (~500 kDa). At confluence FAM neither colocalized with, nor immunoprecipitated, β-catenin or E-cadherin, which were predominantly in a larger molecular weight complex (~2 MDa) at the cell surface. Overexpression of FAM in MCF-7 epithelial cells resulted in increased β-catenin levels, which localized to the plasma membrane. Expression of E-cadherin in L-cell fibroblasts resulted in the relocalization of FAM from the Golgi to cytoplasmic puncta. These data strongly suggest that FAM associates with E-cadherin and β-catenin during trafficking to the plasma membrane.

A Bias in ML Estimates of Branch Lengths in the Presence of Multiple Signals

Sequence data often have competing signals that are detected by network programs or Lento plots. Such data can be formed by generating sequences on more than one tree, and combining the results, a mixture model. We report that with such mixture models, the estimates of edge (branch) lengths from maximum likelihood (ML) methods that assume a single tree are biased. Based on the observed number of competing signals in real data, such a bias of ML is expected to occur frequently. Because network methods can recover competing signals more accurately, there is a need for ML methods allowing a network. A fundamental problem is that mixture models can have more parameters than can be recovered from the data, so that some mixtures are not, in principle, identifiable. We recommend that network programs be incorporated into best practice analysis, along with ML and Bayesian trees.

Rapid prototyping framework for visual control of autonomous micro aerial vehicles

Rapid prototyping environments can speed up the research of visual control algorithms. We have designed and implemented a software framework for fast prototyping of visual control algorithms for Micro Aerial Vehicles (MAV). We have applied a combination of a proxy-based network communication architecture and a custom Application Programming Interface. This allows multiple experimental configurations, like drone swarms or distributed processing of a drone's video stream. Currently, the framework supports a low-cost MAV: the Parrot AR.Drone. Real tests have been performed on this platform and the results show comparatively low figures of the extra communication delay introduced by the framework, while adding new functionalities and flexibility to the selected drone. This implementation is open-source and can be downloaded from www.vision4uav.com/?q=VC4MAV-FW

UHT milk contains multiple forms of αS1-casein that undergo degradative changes during storage

Milk proteins are susceptible to chemical changes during processing and storage. We used proteomic tools to analyse bovine αS1-casein in UHT milk. 2-D gels of freshly processed milk αS1-casein was presented as five or more spots due to genetic polymorphism and variable phosphorylation. MS analysis after phosphopeptide enrichment allowed discrimination between phosphorylation states and genetic variants. We identified a new alternatively-spliced isoform with a deletion of exon 17, producing a new C-terminal sequence, K164SQVNSEGLHSYGL177, with a novel phosphorylation site at S174. Storage of UHT milk at elevated temperatures produced additional, more acidic αS1-casein spots on the gels and decreased the resolution of minor forms. MS analysis indicated that non-enzymatic deamidation and loss of the N-terminal dipeptide were the major contributors to the changing spot pattern. These results highlight the important role of storage temperature in the stability of milk proteins and the utility of proteomic techniques for analysis of proteins in food.

Design of a knowledge base to teach programming

Programming is a subject that many beginning students find difficult. This paper describes a knowledge base designed for the purpose of analyzing programs written in the PHP web development language. The aim is to use this knowledge base in an Intelligent Tutoring System that will provide effective feedback to students. The main focus of this research is that a programming exercise can have many correct solutions. This paper presents an overview of how the proposed knowledge base can be utilized to accept different solutions to a given exercise