Polarized fluid movement and not cell death, creates luminal spaces in adult prostate epithelium

There are two predominant theories for lumen formation in tissue morphogenesis: cavitation driven by cell death, and membrane separation driven by epithelial polarity. To define the mechanism of lumen formation in prostate acini, we examined both theories in several cell lines grown in three-dimensional (3D) Matrigel culture. Lumen formation occurred early in culture and preceded the expression of cell death markers for apoptosis (active caspase 3) and autophagy (LC-3). Active caspase 3 was expressed by very few cells and inhibition of apoptosis did not suppress lumen formation. Despite LC-3 expression in all cells within a spheroid, this was not associated with cell death. However, expression of a prostate-secretory protein coincided with lumen formation and subsequent disruption of polarized fluid movement led to significant inhibition of lumen formation. This work indicates that lumen formation is driven by the polarized movement of fluids and proteins in 3D prostate epithelial models and not by cavitation.

Sublime acts : desire in the studio

Acknowledging the recent call to review design creativity and consideration of the body's affective states in education, this paper explores how desire, conceptualized as an immanent force (Deleuze & Guattari, 1987) and an irresistible force (Burke, 1753) can be a means of deeper engagement within the design studio. Positing 'disruption or blockage' as a key agent which propels subjects from fields of normalcy to fields of otherness, and subsequently mobilises distinct modes of desire, this paper takes Edmund Burke's Romantic sublime and Patricia Yaeger's feminine sublime as critical lenses through which to review a first year interior program posited around the body. The paper highlights how the embodiment of 'desirous processes' within the design program and relational encounters within the studio represent an overarching pedagogical 'hinge' (Ellsworth, 2005). Rather than being a point of beginning, the start of first year is seen and experienced as a threshold opening to a new rhythm in a proces of becoming that is already underway.

Subacute effects of ecstasy on mood : an exploration of associated risk factors

Ecstasy use may result in lowered mood, anxiety or aggression in the days following use. Yet, few studies have investigated what factors increase the risk of experiencing such symptoms. Ecstasy users (at least once in the last 12 months) who subsequently took ecstasy (n=35) over the next week, were compared on measures of mood, sleep, stress and drug use, with those who abstained (n=21) that week. Measures were administered the week prior to ecstasy use and 1 and 3 days following use, or the equivalent day for abstainers. Mood symptoms were assessed using the Kessler-10 self-report psychological distress scale, a subjective mood rating (1-10), and the depression, anxiety and hostility items of the clinician-rated Brief Psychiatric Rating Scale. Timeline followback methods were used to collect information on drug use and life stress in the past month. Self-reported sleep quality was also assessed. Ecstasy use was not associated with subacute depressive, anxiety or aggressive symptoms. Rather, lowered mood and increased psychological distress were associated with self-reported hours and quality of sleep obtained during the 3-day follow up. These findings highlight the importance of considering sleep disruption in understanding the short-term mood effects of ecstasy use.

The Ghrelin axis : does it have an appetite for cancer progression?

Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHSR), is a peptide hormone with diverse physiological roles. Ghrelin regulates GH release, appetite and feeding, gut motility, and energy balance and also has roles in the cardiovascular, immune, and reproductive systems. Ghrelin and the GHSR are expressed in a wide range of normal and tumor tissues, and a fluorescein-labeled, truncated form of ghrelin is showing promise as a biomarker for prostate cancer. Plasma ghrelin levels are generally inversely related to body mass index and are unlikely to be useful as a biomarker for cancer, but may be useful as a marker for cancer cachexia. Some single nucleotide polymorphisms in the ghrelin and GHSR genes have shown associations with cancer risk; however, larger studies are required. Ghrelin regulates processes associated with cancer, including cell proliferation, apoptosis, cell migration, cell invasion, inflammation, and angiogenesis; however, the role of ghrelin in cancer is currently unclear. Ghrelin has predominantly antiinflammatory effects and may play a role in protecting against cancer-related inflammation. Ghrelin and its analogs show promise as treatments for cancer-related cachexia. Further studies using in vivo models are required to determine whether ghrelin has a role in cancer progression.

IGF2 increases de novo steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Long terminal repeats act as androgen-responsive enhancers for the PSA-Kallikrein locus

The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasize the importance of repetitive elements as functional regulatory units

Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia

Context: The benefits of high serum levels of 25-hydroxyvitamin D [25(OH)D] are unclear. Trials are needed to establish an appropriate evidence base. Objective: We plan to conduct a large-scale trial of vitamin D supplementation for the reduction of cancer incidence and overall mortality and report here the methods and results of a pilot trial established to inform its design. Design: Pilot D-Health was a randomized trial carried out in a general community setting with 12 months intervention and follow-up. Participants: Participants were 60- to 84-yr-old residents of one of the four eastern Australian states who did not have any vitamin D-related disorders and who were not taking more than 400 IU supplementary vitamin D per day. A total of 644 participants were randomized, and 615 completed the study (two persons withdrew because of nonserious adverse events). Interventions: The interventions were monthly doses of placebo or 30,000 or 60,000 IU vitamin D3. Main Outcomes: The main outcomes were the recruitment rate and changes in serum 25(OH)D. Results: Ten percent of those approached were recruited. At baseline, the mean 25(OH)D was 42 nmol/liter in all three study arms. The mean change in 25(OH)D in the placebo group was 0.12 nmol/liter, compared with changes of 22 and 36 nmol/liter in the 30,000- and 60,000-IU groups, respectively. Conclusions: The D-Health pilot has shown that a large trial is feasible in Australia and that a dose of 2000 IU/d will be needed to ensure that a large proportion of the population reaches the target serum 25(OH)D level. Copyright © 2012 by The Endocrine Society.

Affect and inarticulacy : the silent voice of the artist

This paper is based on a practice-led research project I conducted into the artist’s ‘voice’ as part of my PhD. The artist’s ‘voice’ is, I argue, comprised of a dual motivation—'articulate' representation and ‘inarticulate’ affect—two things which do not necessarily derive from the artist; two things that are in effect, trans-subjective. Within this paper I will explore the ‘inarticulate’ through the later Lyotard’s affect-phrase, in conjunction with the example of my own painting and digital arts practice, to show just how this unknown can be mapped and understood as generative. As a visual artist my primary interest is in abstraction; I am curious about the emergence of pictorial significance and content from affect’s seemingly unknowable space. My studio practice occasions a sense of borderlessness, and uncertainty where each work or body of work ‘leaks’ into the next, exploring the unfamiliar through the powerful and restless discursive silence of affect. It is within this silence that is performed the disturbing yet generative disconnect that is the affect-phrase. This I contend is apparent in art’s manifest materiality that is, its degree of abstraction and muteness. For the later Lyotard, affect disrupts articulation by injuring or violating the rules of the genres of discourse. For this to be evident one needs to attend to the subtleties of how affect may ‘animate’ discourse. In other words how affect’s discursive disruption activates art’s resistance to definitive interpretation generating even demanding diverse ‘meaning’ creation for art, the abstract, and critical discourse.

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.

Sustainability in post disaster road infrastructure recovery projects in Queensland, Australia

between mid 2010 and early 2011, Queensland road related infrastructures were devastated by flood and cyclone related natural disasters. Responding to these recent events and in preparing for more regular and intense climate-change induced events in future, the Queensland Government is now reviewing how post-disaster road infrastructure recovery projects are planned and delivered. In particular, there is awareness that rebuilding such infrastructure need sustainable strategies across economic, environmental and social dimensions. A comprehensive sustainability assessment framework for pre and post disaster situations can minimize negative impact on our communities, economy and environment. This research is underway to develop a comprehensive sustainability element frame work for post disaster management in road infrastructures in Queensland, Australia. Analyzing the implications of disruption to transport network and associated services is an important part of preparing local and regional responses to the impacts of natural disasters. This research can contribute to strategic planning, management leading to safe, efficient and integrated transport system that supports sustainable economic, social and environmental outcomes in Queensland. Within this context, this paper provides an overview of the qualitative mixed-method research approach involving literature reviews and case studies to explore and evaluate a number of sustainability elements with a view to develop operational strategies for disaster recovery road projects.

Diabetes health program development for Aboriginal and Torres Strait Islander women

According to Australian Health (2008), the area of endocrine, nutritional and metabolic disorders (mainly diabetes) yields the highest cause of death for Indigenous Australian women at 10.1%. Indigenous Brisbane North women’s results reiterate this with slightly higher percentages and are a cause for concern and action due to the noted levels of undiagnosed/unaware Indigenous Brisbane North women with abnormal blood glucose levels, whom participated in the research. A sub-sample of the group (N=17) were piloted to test the feasibility of method of eliciting health information on Indigenous Women within this community. This pilot study revealed the following health information regarding this group of women. 41.2% of Indigenous Brisbane North women were found to have blood glucose levels that were outside normal ranges, however only 29.4% had been diagnosed with diabetes and or endocrine abnormalities. These findings highlight that 11.8% of participants have signs indicating that they may have undiagnosed diabetes or/and pre diabetes juxtaposed to unacceptable endocrine levels compatible with health and wellness. The percentages of Indigenous Brisbane North Women whom have indicated that they have a diagnosis of diabetes have been compared to both National Indigenous peoples percentages and the national percentages for the wider Australian community (all Australians). The rate of diabetes within this population is 9 times that of the wider Australian community and 5 times that of the wider Australian Indigenous community. Data was collected from Indigenous participants on arrival and the attendance numbers of 112 women was recorded for comparison with other current health prevention wellness programs being delivered. Data was also collected through the use of specially designed culturally safe questionnaires undertaken in conjunction with health checks and health service information given to participants.

The relationship between anti-mullerian hormone in women receiving fertility assessments and age at menopause in subfertile women : evidence from large population studies

Context: Anti-Müllerian hormone (AMH) concentration reflects ovarian aging and is argued to be a useful predictor of age at menopause (AMP). It is hypothesized that AMH falling below a critical threshold corresponds to follicle depletion, which results in menopause. With this threshold, theoretical predictions of AMP can be made. Comparisons of such predictions with observed AMP from population studies support the role for AMH as a forecaster of menopause. Objective: The objective of the study was to investigate whether previous relationships between AMH and AMP are valid using a much larger data set. Setting: AMH was measured in 27 563 women attending fertility clinics. Study Design: From these data a model of age-related AMH change was constructed using a robust regression analysis. Data on AMP from subfertile women were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect- EPIC) cohort (n � 2249). By constructing a probability distribution of age at which AMH falls below a critical threshold and fitting this to Prospect-EPIC menopausal age data using maximum likelihood, such a threshold was estimated. Main Outcome: The main outcome was conformity between observed and predicted AMP. Results: To get a distribution of AMH-predicted AMP that fit the Prospect-EPIC data, we found the critical AMH threshold should vary among women in such a way that women with low age-specific AMH would have lower thresholds, whereas women with high age-specific AMH would have higher thresholds (mean 0.075 ng/mL; interquartile range 0.038–0.15 ng/mL). Such a varying AMH threshold for menopause is a novel and biologically plausible finding. AMH became undetectable (�0.2 ng/mL) approximately 5 years before the occurrence of menopause, in line with a previous report. Conclusions: The conformity of the observed and predicted distributions of AMP supports the hypothesis that declining population averages of AMH are associated with menopause, making AMH an excellent candidate biomarker for AMP prediction. Further research will help establish the accuracy of AMH levels to predict AMP within individuals.

Characterization of inflammatory responses to eccentric exercise in humans

Eccentric exercise commonly results in muscle damage. The primary sequence of events leading to exercise-induced muscle damage is believed to involve initial mechanical disruption of sarcomeres, followed by impaired excitation-contraction coupling and calcium signaling, and finally, activation of calcium-sensitive degradation pathways. Muscle damage is characterized by ultrastructural changes to muscle architecture, increased muscle proteins and enzymes in the bloodstream, loss of muscular strength and range of motion and muscle soreness. The inflammatory response to exercise-induced muscle damage is characterized by leukocyte infiltration and production of pro-inflammatory cytokines within damaged muscle tissue, systemic release of leukocytes and cytokines, in addition to alterations in leukocyte receptor expression and functional activity. Current evidence suggests that inflammatory responses to muscle damage are dependent on the type of eccentric exercise, previous eccentric loading (repeated bouts), age and gender. Circulating neutrophil counts and systemic cytokine responses are greater after eccentric exercise using a large muscle mass (e.g. downhill running, eccentric cycling) than after other types of eccentric exercise involving a smaller muscle mass. After an initial bout of eccentric exercise, circulating leukocyte counts and cell surface receptor expression are attenuated. Leukocyte and cytokine responses to eccentric exercise are impaired in elderly individuals, while cellular infiltration into skeletal muscle is greater in human females than males after eccentric exercise. Whether alterations in intracellular calcium homeostasis influence inflammatory responses to muscle damage is uncertain. Furthermore, the effects of antioxidant supplements are variable, and the limited data available indicates that anti-inflammatory drugs largely have no influence on inflammatory responses to eccentric exercise. In this review, we compare local versus systemic inflammatory responses, and discuss some of the possible mechanisms regulating the inflammatory responses to exercise-induced muscle damage in humans.

Observation of bus ridership in the aftermath of the 2011 Floods in Southeast Queensland, Australia

The 2011 floods in Southeast Queensland had a devastating impact on many sectors including transport. Road and rail systems across all flooded areas of Queensland were severely affected and significant economic losses occurred as a result of roadway and railway closures. Travellers were compelled to take alternative routes because of road closures or deteriorated traffic conditions on their regular route. Extreme changes in traffic volume can occur under such scenarios which disrupts the network re-equilibrium and re-stabilisation in the recovery phase as travellers continuously adjust their travel options. This study explores how travellers respond to such a major network disruption. A comprehensive study was undertaken focusing on how bus riders reacted to the floods in Southeast Queensland by comparing the ridership patterns before, during and after the floods. The study outcomes revealed the evolving reactions of transit users to direct and indirect impacts of a natural disaster. A good understanding of this process is crucial for developing appropriate strategies to encourage modal shift of automobile users to public transit and also for modelling of travel behaviours during and after a major network disruption caused by natural disasters.