Research Report 2004–2005

The National Health and Medical Research Council Clinical Trials Centre has the purpose of improving outcomes in health through clinical trials research. It was established by the National Health and Medical Research Council in 1988 as a research centre at the University of Sydney. The CTC provides the knowledge and infrastructure to ensure the quality, timely completion and reporting of clinical trials. It has vast expertise in the design, conduct and analysis of randomised controlled trials, particularly in cancer and cardiovascular disease. Over 100 staff have specialised skills, taking in clinical trials design, biostatistics, database design, randomisation and drug distribution, outcome assessment, quality assurance, and regulatory and ethical issues. In the past 16 years, the CTC has participated in more than 50 investigatorinitiated, collaborative-group clinical trials and coordinated some of the largest randomised trials initiated by Australian investigators (LIPID and FIELD studies, each with over 9000 patients). Over 40 000 patients have been randomised to these trials. All clinical trials undertaken through the CTC are conducted strictly according to guidelines for clinical trials research and conduct, and are audited by sponsors, the CTC itself and regulatory authorities. The CTC has a history of working collaboratively with cooperative groups, clinical trial networks and other organisations, and has played a central role in establishing some of these groups. These activities have been recognised in increased grant funding to enable further collaboration and to increase the number of investigator-initiated trials in Australia. In its research, the CTC has prospered: it has developed strategies for patient recruitment, trial and data management, study coordination, information systems and randomisation in an environment of academic excellence. In addition to trials management, the CTC is a leader in biostatistical methodology and analysis and in systematic review of health evidence. The integrated expertise of the CTC staff is turned to good use in frequent educational activities in Australia and elsewhere. This report covers the CTC’s achievements for the biennium, 2004–2005

Unraveling DNA tori under tension

Motivated by recent experiments, we develop a model for DNA toroids under external tension. We find that tori are the equilibrium states for our model up to a critical tension, above which they become only metstable. Above this tension, we find a cascade of transitions between discrete toroid states that successively lowers the winding number, until the ground state (rod) is reached. In this process, this model predicts a nearly constant force plateau as a function of extension, in agreement with experiment.Comment: 9 pages, 11 figure

Mdm2 Induces Mono-Ubiquitination of FOXO4

Background: The Forkhead box O (FOXO) class of transcription factors are involved in the regulation of several cellular responses including cell cycle progression and apoptosis. Furthermore, in model organisms FOXOs act as tumor suppressors and affect aging. Previously, we noted that FOXOs and p53 are remarkably similar within their spectrum of regulatory proteins [1]. For example, the de-ubiquitinating enzyme USP7 removes ubiquitin from both FOXO and p53. However, Skp2 has been identified as E3 ligase for FOXO1, whereas Mdm2 is the prime E3 ligase for p53. Principal Findings/Methodology: Here we provide evidence that Mdm2 acts as an E3 ligase for FOXO as well. In vitro incubation of Mdm2 and FOXO results in ATP-dependent (multi)mono-ubiquitination of FOXO similar to p53. Furthermore, in vivo co-expression of Mdm2 and FOXO induces FOXO mono-ubiquitination and consistent with this result, siRNAmediated depletion of Mdm2 inhibits mono-ubiquitination of FOXO induced by hydrogen peroxide. Regulation of FOXO ubiquitination by Mdm2 is likely to be direct since Mdm2 and FOXO co-immunoprecipitate. In addition, Mdm2-mediated ubiquitination regulates FOXO transcriptional activity. Conclusions/Significance: These data identify Mdm2 as a novel E3 ligase for FOXOs and extend the analogous mode o

Risk Factors for Mortality Due to Shigellosis: A Case-Control Study Among Severely-malnourished Children in Bangladesh

To determine the risk factors for death of severely-malnourished Bangladeshi children with shigellosis, a case-control study was conducted at the Clinical Research and Service Centre of ICDDR,B: Centre for Health and Population Research in Dhaka, Bangladesh. One hundred severely-malnourished children (weight-for-age <60% of median of the National Center for Health Statistics), with a positive stool culture for Shigella dysenteriae type 1 or S. flexneri, who died during hospitalization, were compared with another 100 similar children (weight-for-age <60% and with S. dysenteriae type 1 or S. flexneri-associated infection) discharged alive. Children aged less than four years were admitted during December 1993 - January 1999. The median age of the cases who died or recovered was 9 months and 12 months respectively. Bronchopneumonia, abdominal distension, absent or sluggish bowel sound, clinical anaemia, altered consciousness, hypothermia, clinical sepsis, low or imperceptible pulse, dehydration, hypoglycaemia, high creatinine, and hyperkalaemia were all significantly more frequent in cases than in controls. In multivariate regression analysis, altered consciousness (odds ratio [OR]=2.6, 95% confidence interval [CI] 1.0-6.8), hypoglycaemia (blood glucose <3 mmol/L (OR= 7.8, 95% CI 2.9-19.6), hypothermia (temperature <36 \ub0C) (OR = 5.7, 95% CI 1.5-22.1), and bronchopneumonia (OR = 2.5, 95% CI 1.1-5.5) were identified as significant risk factors for mortality. Severely-malnourished children with shigellosis having hypoglycaemia, hypothermia, altered consciousness and/or bronchopneumonia were at high risk of death. Based on the findings, the study recommends that early diagnosis of shigellosis in severely-malnourished children and assertive therapy for proper management to prevent development of hypothermia, hypoglycaemia,bronchopneumonia, or altered consciousness and its immediate treatment are likely to reduce Shigella-related mortality in severely-malnourished children

Class of exactly solvable SO(n) symmetric spin chains with matrix product ground states

We introduce a class of exactly solvable SO(n) symmetric Hamiltonians with matrix product ground states. For an odd $n\geq 3$ case, the ground state is a translational invariant Haldane gap spin liquid state; while for an even $n\geq 4$ case, the ground state is a spontaneously dimerized state with twofold degeneracy. In the matrix product ground states for both cases, we identify a hidden antiferromagnetic order, which is characterized by nonlocal string order parameters. The ground-state phase diagram of a generalized SO(n) symmetric bilinear-biquadratic model is discussed.Comment: 11 pages, 5 figure

Kinetic analysis of a chiral granular motor

We study the properties of a heterogeneous, chiral granular rotor that is capable of performing useful work when immersed in a bath of thermalized particles. The dynamics can be obtained in general from a numerical solution of the Boltzmann-Lorentz equation. We show that a mechanical approach gives the exact mean angular velocity in the limit of an infinitely massive rotor. We examine the dependence of the mean angular velocity on the coefficients of restitution of the two materials composing the motor. We compute the power and efficiency and compare with numerical simulations. We also perform a realistic numerical simulation of a granular rotor which shows that the presence of non uniformity of the bath density within the region where the motor rotates, and that the ratchet effect is slightly weakened, but qualitatively sustained. Finally we discuss the results in connection with recent experiments.Comment: 19 pages, 12 figure