In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumours

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors. Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors. Results:In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm3. In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA. Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.

Modelling the activation of words in human memory : the spreading activation, spooky-activation-at-a-distance and the entanglement models compared

Modelling how a word is activated in human memory is an important requirement for determining the probability of recall of a word in an extra-list cueing experiment. The spreading activation, spooky-action-at-a-distance and entanglement models have all been used to model the activation of a word. Recently a hypothesis was put forward that the mean activation levels of the respective models are as follows: Spreading � Entanglment � Spooking-action-at-a-distance This article investigates this hypothesis by means of a substantial empirical analysis of each model using the University of South Florida word association, rhyme and word norms.

The complete mitochondrial genome of the gall-forming fly, Fergusonina taylori(Nelson and Yeates) (Diptera: Fergusoninidae)

The monogeneric family Fergusoninidae consists of gall-forming flies that, together with Fergusobia (Tylenchida: Neotylenchidae) nematodes, form the only known mutualistic association between insects and nematodes. In this study, the entire 16,000 bp mitochondrial genome of Fergusonina taylori Nelson and Yeates was sequenced. The circular genome contains one encoding region including 27 genes and one non-coding A þT-rich region. The arrangement of the proteincoding, ribosomal RNA (rRNA) and transfer RNA (tRNA) genes was the same as that found in the ancestral insect. Nucleotide composition is highly A þ T biased. All of the protein initiation codons are ATN, except for nad1 which begins with TTT. All 22 tRNA anticodons of F. taylori match those observed in Drosophila yakuba, and all form the typical cloverleaf structure except for tRNA-Ser (AGN) which lacks a dihydrouridine (DHU) arm. Secondary structural features of the rRNA genes of Fergusonina are similar to those proposed for other insects, with minor modifications. The mitochondrial genome of Fergusonina presented here may prove valuable for resolving the sister group to the Fergusoninidae, and expands the available mtDNA data sources for acalyptrates overall.

Letter To Robert Lowell

Poem

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

Anglican Church knew clergyman Robert Waddington was a risk

AUSTRALIAN church officials knew of child-sex allegations in Britain against a senior clergymen when they pushed a victim into accepting a compensation payout on the basis that there was no evidence to back up his claims of abuse. Former Church of England investigator Ray Morris says he prepared a 2004 report about allegations in Britain and Australia - from the 1960s and 80s - against Robert Waddington. He sent it to north Queensland diocese officials, who were at the time involved in mediation with the Australian victim over his claims that he was abused weekly by Waddington between 1964 and 1968, who was headmaster of St Barnabas boarding school in Ravenshoe, southwest of Cairns.

Robert Waddington's cycle of abuse stretches beyond 50 years

THE Church of England banished serial pedophile priest Robert Waddington to Australia, where he abused children across a decade, after suspicions were raised about him molesting choirboys in his London parish. In an alleged church cover-up spanning almost 60 years, Waddington was suddenly and unexpectedly sent to a small school in regional Queensland in 1956 amid claims he was molesting the son of an English politician. Last month the Church of England ordered an independent inquiry into the handling of allegations against Waddington, after a joint investigation by The Australian and The Times of London. But it can now be revealed that Waddington - who died in 2007, facing allegations he abused students in Australia in the 1960s and English choirboys in the 80s and 90s - was molesting children as soon as he joined the church in 1953. The latest allegations have been made by Ray Munn, 70, who was recruited by Waddington, then a curate at St John's church in Bethnal Green, East London, to sing in the choir in 1953. He was almost immediately groomed by the Cambridge University-educated clergyman, who took him on holidays in the English countryside, before he began molesting the then 11-year-old.

Capital cost model for Robert evaporators

ROBERT EVAPORATORS in Australian sugar factories are traditionally constructed with 44.45 mm outside diameter stainless steel tubes of ~2 m length for all stages of evaporation. There are a few vessels with longer tubes (up to 2.8 m) and smaller and larger diameters (38.1 and 50.8 mm). Queensland University of Technology is undertaking a study to investigate the heat transfer performance of tubes of different lengths and diameters for the whole range of process conditions typically encountered in the evaporator set. Incorporation of these results into practical evaporator designs requires an understanding of the cost implications for constructing evaporator vessels with calandrias having tubes of different dimensions. Cost savings are expected for tubes of smaller diameter and longer length in terms of material, labour and installation costs in the factory. However these savings must be considered in terms of the heat transfer area requirements for the evaporation duty, which will likely be a function of the tube dimensions. In this paper a capital cost model is described which provides a relative cost of constructing and installing Robert evaporators of the same heating surface area but with different tube dimensions. Evaporators of 2000, 3000, 4000 and 5000 m2 are investigated. This model will be used in conjunction with the heat transfer efficiency data (when available) to determine the optimum tube dimensions for a new evaporator at a specified evaporation duty. Consideration is also given to other factors such as juice residence time (and implications for sucrose degradation and control) and droplet de-entrainment in evaporators of different tube dimensions.

‘Only a pawn in their game’ : crime, risk and politics in the case of Robert Fardon

In 2003 Robert Fardon was the first prisoner to be detained under the Dangerous Prisoners (Sexual Offenders) Act 2003 (Qld), the first of the new generation preventive detention laws enacted in Australia and directed at keeping sex offenders in prison or under supervision beyond the expiry of their sentences where a court decides, on the basis of psychiatric assessments, that unconditional release would create an unacceptable risk to the community. A careful examination of Fardon’s case shows the extent to which the administration of the regime was from the outset governed by politics and political calculation rather than the logic of risk management and community protection. In 2003 Robert Fardon was the first person detained under the Dangerous Prisoners (Sexual Offenders) Act 2003 (Qld) (hereafter DPSOA), a newly enacted Queensland law aimed at the preventive detention of sex offenders. It was the first of a new generation of such laws introduced in Australia, now also in force in NSW, Western Australia and Victoria. The laws have been widely criticized by lawyers, academics and others (Keyzer and McSherry 2009; Edgely 2007). In this article I want to focus on the details of how the Queensland law was administered in Fardon’s case, he being perhaps the most well-known prisoner detained under such laws and certainly the longest held. It will show, I hope, that seemingly abstract rule of law principles invoked by other critics are not simply abstract: they afford a crucial practical safeguard against the corruption of criminal justice in which the ends both of community protection and of justice give way to opportunistic exploitation of ‘the mythic resonance of crime and punishment for electoral purposes’ (Scheingold 1998: 888).

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Nelson's (1976) Modified Card Sorting Test: A review

We review studies of Nelson's (1976) Modified Card Sorting Test (MCST) that have examined the performance of subjects with frontal lobe dysfunction. Six studies investigated the performance of normal controls and patients with frontal lobe dysfunction, whereas four studies compared the performance of frontal and nonfrontal patients. One further study compared the performance of amnesic patients both on the MCST and on the original Wisconsin Card Sorting Test (WCST). Evidence regarding the MCST's differential sensitivity to frontal lobe dysfunction is weak, as is the evidence regarding the equivalence of the MCST and WCST. It is likely that the MCST is an altogether different test from the standard version. In the absence of proper normative data for the MCST, we provide a table of scores derived from the control groups of various studies. Given the paucity of evidence, further research is required before the MCST can be recommended for use as a marker of frontal lobe dysfunction.

The influence of Lord Robert Baden-Powell on the development of the Boy Scout Movement with observations on its operation in Queensland 1907-1937

The purpose of the Boy Scout Movement was to create boys who were honest, obedient to constituted authority and loyal to the King and the British Empire. This thesis examines the influence that Scouting's founder, Lord Robert Baden-Powell, had on the development of Scouting in Queensland in the period 1907 to 1937, and concludes that that influence was profound. Baden-Powell conceived the Boy Scout Movement, and its non-formal educative method as an answer to some of the social, economic, and political problems at the beginning of the twentieth century – a paradigm recognised and acknowledged by educators of the day.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.