Sediment organic carbon and temperature effects on methylmercury concentration: A mesocosm experiment.

The fate and mobility of mercury, and its bioaccumulation primarily as methylmercury (MeHg), in marine ecosystems are influenced by climate related environmental factors, including increased temperature and carbon loading. To investigate the interactions between sediment organic carbon and temperature MeHg bioaccumulation, mesocosm experiments were conducted examining relationships between sediment, water column and biota (sediment-dwelling amphipod and juvenile oyster) MeHg concentration. Experimental treatments consisted of a two by two design of high and low temperature (15 & 25 °C) and high and low sediment organic carbon (4-5% and 13% LOI, pre-experiment). Sediment organic carbon had significant individual effects on MeHg concentration in water and biota, with higher carbon associated with lower MeHg. Temperature individual effects were significant for sediment, water, and only amphipod MeHg concentration, with higher temperature treatments indicating higher MeHg concentration. There were significant temperature × carbon interactions observed for sediment, dissolved, and oyster MeHg concentration. Sediment carbon reduction had greater influence than temperature on increasing MeHg concentrations in both the water column and biota. MeHg concentrations in the bulk sediment were not correlated with MeHg in the water column or in the biota, indicating that even when sediments are the only source of MeHg, bulk sediment measurements do not provide a good proxy for bioaccumulation and that the concentration in bulk sediments is not the primary determinant of MeHg entry into the food web.

A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study.

BACKGROUND: Intermittent androgen suppression (IAS) is an increasingly popular treatment option for castrate-sensitive prostate cancer. On the basis of previous data with anti-angiogenic strategies, we hypothesized that pan-inhibition of the vascular endothelial growth factor receptor using pazopanib during the IAS off period would result in prolonged time to PSA failure. METHODS: Men with biochemically recurrent prostate cancer, whose PSA was <0.5 ng ml(-1) after 6 months of androgen deprivation therapy were randomized to pazopanib 800 mg daily or observation. The planned primary outcome was time to PSA progression >4.0 ng ml(-1). RESULTS: Thirty-seven patients were randomized. Of 18 patients randomized to pazopanib, at the time of study closure, 4 had progressive disease, 1 remained on treatment and 13 (72%) electively disenrolled, the most common reason being patient request due to grade 1/2 toxicity (8 patients). Two additional patients were removed from treatment due to adverse events. Of 19 patients randomized to observation, at the time of study closure, 4 had progressive disease, 7 remained under protocol-defined observation and 8 (42%) had disenrolled, most commonly due to non-compliance with protocol visits (3 patients). Because of high dropout rates in both arms, the study was halted. CONCLUSIONS: IAS is a treatment approach that may facilitate investigation of novel agents in the hormone-sensitive state. This trial attempted to investigate the role of antiangiogenic therapy in this setting, but encountered several barriers, including toxicities and patient non-compliance, which can make implementation of such a study difficult. Future investigative efforts in this arena should carefully consider drug toxicity and employ a design that maximizes patient convenience to reduce the dropout rate.

Preclinical development of siRNA therapeutics for AL amyloidosis.

Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.

Proliferation is not increased in airway myofibroblasts isolated from asthmatics.

Airway mesenchymal cells, such as myofibroblasts and airway smooth muscle cells, contribute to inflammation, airway remodelling and hyperresponsiveness in asthma by excessive proliferation and inflammatory mediator production. Using endobronchial biopsies obtained from both nonasthmatic and asthmatic subjects, in situ proliferation was assessed by immunostaining for cyclin D1. The number of immunoreactive cells increased with asthma severity and was restricted to the epithelium and subepithelial connective tissue. Despite increases in smooth muscle area, cyclin D1 was not detected in cells in intact muscle bundles. Biopsy-derived cell cultures were characterised as predominantly myofibroblasts, and were assessed to determine whether proliferation and cytokine production varied with asthma status. Cell enumeration showed that basal proliferation was similar in cells from nonasthmatics and asthmatics, and mitogenic responses to fibroblast growth factor-2, thrombin or serum were either reduced or unchanged in cells from asthmatics. Interleukin (IL)-1-dependent granulocyte-macrophage colony-stimulating factor and IL-8 release was increased in cell supernatants from asthmatics. Thus, increased rates of cellular proliferation identified in situ in the asthmatic airway occurred outside the expanded smooth muscle compartment. Although reduced proliferative responses were observed in cultured myofibroblasts from asthmatics, the increased cytokine production by these cells suggests that this contributes to and may perpetuate ongoing inflammation in asthma.

Continuous administration of low-dose GnRH in mares I. Control of persistent anovulation during the ovulatory season.

Three experiments were conducted during the operational breeding season to confirm that continuous, subcutaneous infusion of low-dose GnRH would not disrupt established estrous cycles (Experiment 1), and test the hypotheses that a similar treatment would stimulate secretion of LH and induce development of ovulatory follicles in persistently anovulatory mares (Experiments 2 and 3). Treatment with GnRH (5 microg/h) increased (P<0.001) serum P4 during the luteal phase (7.7+/-0.5 versus 6.4+/-0.5 ng/mL), tended to increase serum LH (2.6+/-0.27 versus 1.9+/-0.25 ng/mL), and did not modify interovulatory intervals. In Experiment 2, GnRH treatment (2.5-5 microg/h) of persistently anovulatory mares increased (P<0.001) serum LH compared to controls (0.5+/-0.08 versus 0.1+/-0.03 ng/mL), with all GnRH-treated and no Control mares ovulating. Mares exhibiting Delayed Recrudescence (n=29) or Lactational Anovulation (n=18), were assigned randomly in Experiment 3 to receive either (1) GnRH/GnRH (n=23); 2.5 microg GnRH/h for 14 d (Period I) and 5 microg/h during the subsequent 28 d (Periods II and III); or (2) Control/GnRH (n=24); no treatment during Period I (control period) and GnRH treatments as in 1 during Periods II and III. Percentage of mares ovulating and pregnant during Period I was greater (P<0.05) for GnRH-treated than Control mares. Thereafter, cumulative ovulation frequency (85%), pregnancy (72%) and cycles/conception (1.3+/-0.2) were similar between groups; however, interval to conception was reduced (P<0.01) by 10.3 d in GnRH/GnRH compared to Control/GnRH.

The PPARgamma ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation.

There is considerable interest in the role of peroxisome proliferator activated receptors (PPARs) as ligand-activated transcription factors in the airways. This study examines the effects of a potent synthetic PPARgamma ligand, rosiglitazone (RG), in a murine model of allergen-induced inflammation, to explore its potential regulation of airways inflammation, structure and function. C57BL/6 mice were sensitised with ovalbumin (OVA, 50 microg i.p., days 0, 12) and challenged with aerosolized OVA (1% w v(-1), 30 min day(-1)) for 7 days (days 20-26). Mice were treated with RG (5 mg kg(-1) i.p.) or vehicle during the challenge period. The OVA challenge induced increases in leukocyte number and MMP-2 activity in bronchoalveolar lavage fluid and in goblet cell number in lung tissue obtained on Day 27. RG failed to inhibit inflammatory cell infiltration, MMP-2 activity or goblet cell hyperplasia. Respiratory resistance in response to methacholine (MCh i.v.) was greater in OVA-challenged mice than saline-challenged mice and this airways hyperresponsiveness (AHR) was reduced by RG. However, RG did not affect MCh-induced contraction in isolated guinea-pig tracheal rings, nor did it influence the airway obstruction induced by MCh in saline-challenged mice, so a direct effect on airway obstruction is unlikely. These data suggest that RG modulates AHR in this model, by a mechanism that is also potentially independent of an anti-inflammatory action.

Engaging Australian physicians in evidence-based medicine: a representative national survey.

AIM: To assess Australian adult physicians' views about evidence-based medicine (EBM) and quality improvement (QI). BACKGROUND: Cross-sectional postal survey of two hundred and forty-four randomly selected Australian physicians (78.5% response rate). METHOD: Physicians' views about the promotion of EBM and QI and their impact on patient care, strategies to support better clinical practice and self-reported understanding of EBM terms. RESULTS: Sixty-eight per cent (95% confidence interval (CI): 62-74%) of physicians had a positive view of the current promotion of EBM in Australia. Significantly fewer (45%; 95% CI: 38-51%) were so positive about QI (P <0.001). Although 74% (95% CI: 68-79%) indicated that EBM improves patient care, significantly fewer (46%; 95% CI: 40-53%) held this view with respect to QI (P <0.001). Although 70% (95% CI: 64-76%) of physicians agreed they had adequate skills to search for evidence, significantly fewer (21%; 95% CI: 17-27%) agreed they had sufficient time to do so (P <0.001). EBM skills were positively associated with involvement in teaching. Physicians were significantly more positive about approaches exclusive to themselves compared with those involving other disciplines. CONCLUSIONS: Although Australian physicians have positive views of EBM, QI appears less well regarded. Initiatives to improve quality and safety that incorporate principles and language of EBM will likely be received better by physicians than isolated QI. Further enhancement of EBM requires concomitant attention to physician training, workplace infrastructure and supportive professional development.

Does a deadline improve men's participation in self-administered health surveys? A randomized controlled trial in general practice.

BACKGROUND: Self-administered questionnaires are commonly used in experimental studies to elicit quality of life or other outcomes. Hence, achieving an acceptable level of follow-up from patients is critical to minimizing bias. Many methods for maximizing follow-up remain untested. It is also unclear what level of follow-up is required to prevent bias being introduced. METHODS: We recruited 246 men from general practice surgeries in Sydney, Australia. These 246 men were randomized to receive a covering letter with their follow-up questionnaire either advising of a deadline to reply (Deadline, n = 126) or a standard letter without a deadline (No Deadline, n = 120). Four standardized reminder prompts subsequently were administered. We calculated interim response rates and the final proportion of follow-up questionnaires received according to group. We also compared scores on two main outcomes, namely, knowledge and decisional conflict at each time when reminder prompts were administered. RESULTS: One hundred and twelve (88.9%) men in the Deadline group returned their follow-up questionnaires compared with 102 (85.0%) men in the No Deadline group. This difference was not statistically significant [odds ratio = 1.41, 95% confidence interval (CI) = 0.67-2.99; p = 0.36]. Time to response also was not significantly affected by cover letter received (hazard ratio = 0.96; 95% CI = 0.73-1.25; p = 0.76). Results of the original RCT were similar in terms of direction and effect size at all times irrespective of when reminder prompts were administered. CONCLUSION: The addition of a deadline adds no further impact in improving response rates from male patients compared with an unspecified letter. Despite the accepted wisdom that higher response protects against bias, differences in outcomes were consistent throughout the post-test data collection period.

Does evidence-based information about screening for prostate cancer enhance consumer decision-making? A randomised controlled trial.

OBJECTIVES: Efforts to educate men about the controversy surrounding prostate cancer screening are well intended but rarely evaluated rigorously. We evaluated an evidence-based (EB) booklet for men designed to promote informed decision-making. We also determined whether men's preference for involvement in decision-making ("passive", "collaborative" or "active") modified its impact. SETTING AND METHODS: Men aged 40-70 years were recruited from the practices of 13 local general practitioners (GPs) in Sydney, Australia. They completed a self-administered questionnaire before seeing their GP, who, according to pre-randomised codes, distributed either our EB booklet or conventional information. Post-test questionnaires were mailed to men three days later. Of the 248 eligible men recruited, 214 (86% response rate) returned post-test questionnaires. Knowledge of evidence and of risk of developing and dying from prostate cancer, attitudes, interest in screening for prostate-specific antigen (PSA), worry and decisional conflict were the main outcome measures. RESULTS: Compared with those receiving conventional information, men receiving the EB booklet had significantly improved knowledge (50% of items correct, 95% CI 46-53%; vs 45% correct, 95% CI 42-48%) (p = 0.048) and lower levels of decisional conflict (mean 21.6, 95% CI 20.7-22.5; vs mean 24.3, 95% CI 23.4-25.2) (p < 0.001). Interest in PSA screening was significantly reduced in both groups at post-test (p < 0.001). Men preferring a "passive" approach to decision-making gained as much from our EB booklet as those with "active" or "collaborative" preferences. CONCLUSIONS: Our findings show the benefits of providing evidence-based information to men about PSA screening. Our EB booklet facilitated informed choice, even among "passive" decision-makers.

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor alpha.

The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERalpha or mutant(351)ERalpha. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10(-9) or 10(-8) M oestradiol; with 10(-6) M 4-hydroxytamoxifen; with 10(-6) M raloxifene; with 10(-6) M idoxifene, with 10(-6) M EM 652, with 10(-6) M GW 7604; with 5 x 10(-5) M resveratrol and with 10(-6) M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERalpha and clustered together with EM 652 for cells expressing mutant(351)ERalpha. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

Randomized, controlled trials in surgery: perceived barriers and attitudes of Australian colorectal surgeons.

PURPOSE: Although the randomized, controlled trial has gained preeminence as the criterion standard for evaluating pharmaceutical treatments, randomized controlled trials in surgery have been perceived as difficult to surmount. Furthermore, attitudes of surgeons toward randomized, controlled trials are not well understood. We determined the views of Australian surgeons about feasibility of and barriers to surgical randomized trials. METHODS: All members of the Section of Colon and Rectal Surgery of the Royal Australasian College of Surgeons (n = 147) and all Australian colorectal subspecialist surgeons (n = 72) were mailed a questionnaire that included questions about surgical randomized, controlled trials. RESULTS: A total of 195 surgeons responded (89 percent). Two-thirds (66.7 percent; 95 percent confidence interval 59.5-73.1) of respondents agreed that "Randomized controlled trials should be the study design of choice" to evaluate new surgical procedures. Only 19 percent (95 percent confidence interval 13.9-25.3) endorsed the statement that "too much emphasis is placed on results of randomized controlled trials." Barriers to conducting surgical randomized, controlled trials identified by the majority included insufficient funding (74.4 percent; 95 percent confidence interval 67.5-80.2), a lack of support from the wider surgical community (55.9 percent; 95 percent confidence interval 48.6-62.9), and difficulties in convincing patients to accept random allocation to treatment (62.6 percent; 95 percent confidence interval 55.3-69.3). CONCLUSION: These results reveal positive attitudes among Australian surgeons toward randomized, controlled trials, although concerns about the feasibility of randomized, controlled trials have been reinforced.

Evidence-based medicine in general practice: beliefs and barriers among Australian GPs.

If implemented, evidence-based medicine (EBM) in general practice will improve health outcomes for patients. This paper examines the views of 60 Australian general practitioners about EBM. While 57% of respondents had a computer in their surgery, 15% had Internet access and only 3% had access to the Cochrane Library at work. The most commonly cited barrier to EBM was 'patient demand for treatment despite lack of evidence for effectiveness' (45%). The next three most highly rated barriers related to lack of time. For each of three tasks of EBM, namely searching for evidence, appraising evidence and discussing the implications of evidence with patients, lack of time was rated as a 'very important barrier' by significantly more participants than lack of skills (McNemar's tests: chi2(1) = 7.1, P = 0.008, chi2(1) = 14.0, P = 0.001 and chi2(1) = 9.0, P = 0.003, respectively). Preferred resources for EBM included clinical practice guidelines (rated as 'very useful' by 55%) and journals that summarize research evidence, for example Evidence-based Medicine (52%). Systematic reviews were considered 'very useful' by only 15% of respondents, consistent with our finding that 30% did not understand the term 'systematic review'. Furthermore, 43% did not understand 'meta-analysis'. A minority indicated they understood the terms 'relative risk' (23%), 'absolute risk' (28%) and 'number needed to treat' (15%) sufficiently to explain to others. Skills development is crucial to achieve EBM in general practice.

Feeding activity, absorption efficiency and suspension feeding processes in the ascidian, Halocynthia pyriformis (Stolidobranchia: Ascidiacea): responses to variations in diet quantity and quality.

The benthic suspension feeding ascidian, Halocynthia pyriformis (Rathke, 1806), is often exposed to high concentrations of resuspended sediment in the Bay of Fundy. Resuspended sediment can change diet quantity and quality that may alter the ascidian's ability to feed and gain energy. The feeding activity of H. pyriformis exposed to bottom sediment was examined using standard physiological techniques and video endoscopy. Ascidians were exposed to natural seston plus additions of bottom sediment ranging in concentration from 0 to 46 mg l(-1). For each sediment concentration, clearance rate, ingestion rate, and retention efficiency of the ascidians was estimated using flow-through feeding chambers. Samples of suspended particles and feces were collected to estimate absorption efficiency and absorption rate. Results indicate that with increasing sediment concentration, ingestion rate increased to a constant level, absorption rate increased linearly despite a logarithmic decrease in absorption efficiency, and the retention of small particles (2-5 &mgr;m) increased while retention of larger particles (5-15 &mgr;m) decreased. As sediment concentration increased, squirting frequency increased and diameter of the siphon was reduced. Endoscopic observation of feeding structures and processes and the measurement of particle velocity was performed on ascidians exposed to 0 and 10 mg l(-1) of bottom sediment. An increase in squirting frequency at the high concentration facilitated the rejection of unwanted material and altered the structure and transport velocity of mucus. Mucus velocity was five times slower at 10 mg l(-1) than at 0 mg l(-1), however, the overall distance of mucus travel and the probability of clogging was reduced at 10 mg l(-1). H. pyriformis appears to compensate for episodic changes in the quantity and quality of available food particles by altering siphon-opening diameter, squirting frequency, structure and transport of mucus, and retention efficiency to maintain constant clearance rates.

Will donations to their learned college increase surgeons' participation in surveys? A randomized trial.

Effective strategies to maximize response rates to self-administered surveys of clinicians are crucial to minimize response bias. Offers of charitable donations have been assessed for their potential to promote participation of community samples but not in the context of medical specialist samples. We randomized all Australian colorectal surgeons (n = 219) to whom we mailed a survey about clinical practice guidelines to receive either a standard covering letter or one promising a donation to their peak professional organization upon our receipt of their completed survey. Contrary to expectations, surgeons advised that their participation would secure a donation to their college were significantly less likely to return their questionnaire (84.3%, 95% CI 76.0-90.5%) than those receiving a standard letter (93.7%, 95% CI 87.4-97.4%). They also were more tardy in their response (Hazard Ratio = 0.75, 95% CI 0.57-1.00) (P = 0.047). In this context, offering donations to surgeons was counterproductive in enhancing response rates.

Implementing guidelines for smoking cessation advice in Australian general practice: opinions, current practices, readiness to change and perceived barriers.

OBJECTIVE: The aim of this study was to ascertain opinions, current practices, likely readiness to change and perceived barriers to change among Australian GPs in order to develop a plan to implement national guidelines for smoking cessation advice. METHOD: A postal survey of randomly selected GPs in New South Wales, Australia was carried out. RESULTS: We received 311 returned questionnaires (73% response rate). Only 34% of respondents reported providing cessation advice during every routine consultation with a smoker, in accordance with national guidelines. Specific evidence-based approaches recommended in guidelines were under-utilized, with only 54% 'always' or 'frequently' arranging follow-up, 32% providing written materials and 28% setting a 'quit date'. Respondents were no more likely to advise quitting completely than the less effective method of nicotine fading. More than one in four respondents (28%) indicated readiness to change their behaviour. Respondents rated their patients' lack of motivation and uninterest as the most important barriers to smoking cessation advice in general practice. Neither uncertainty about effective smoking cessation strategies nor lack of reimbursement for smoking cessation advice were identified as barriers. CONCLUSIONS: A multicomponent intervention to address suboptimal behaviour and barriers as revealed by this survey holds considerable potential to plan effective implementation of smoking cessation guidelines in general practice. The use of readiness to change as a tool to 'individualize' strategies for guideline implementation should be explored.

Does type of surgeon matter in rectal cancer surgery? Evidence, guideline consensus and surgeons' views.

One of the most obvious but controversial trends in contemporary surgical practice is that of subspecialization. There is a lack of definitive evidence that subspecialization improves cancer outcomes largely because previous research is compromised by confounding variables of referral practice, lack of standardized definitions of surgical skills and selection bias. Randomized controlled trials of generalized versus subspecialist surgical care are unlikely ever to be performed. The present study of surgeons' views about the role of subspecialization in the care of colorectal cancer patients demonstrates partisan reactions among surgeons themselves (89% response rate). Results of national audits will contribute to wider debate about surgical subspecialization in colorectal cancer.

Outcomes from NHMRC public health research project grants awarded in 1993.

AIMS: In 1987, the Public Health Research and Development Committee (PHRDC) was established by the NHMRC as one mechanism to fund public health research in Australia. In 1993, it awarded 32 new and 31 continuing project grants. Given increasing interest in research accountability in Australia, we designed an audit to determine outcomes from this investment. We also explored grant recipients' views about sources of research funding and strategies to enhance research dissemination. METHOD: Self-administered survey, July 1999. MAIN RESULTS: We obtained a 69% response fraction. The majority of projects already had been completed with peer-reviewed articles the most common outputs. More than half (58%) of respondents 'strongly agreed' or 'agreed' that their research had influenced policy to improve public health and 69% that it had influenced practice. Study design was significantly associated with peer-reviewed output, whether self-reported (p=0.002) or corroborated by us (p=0.004). With respect to research funding, significantly more agreed that the NHMRC should enhance program grants for public health research than mechanisms through the Strategic Research Development Committee (p=0.013). The most highly rated strategy to enhance dissemination was greater demand for research results among policy makers. CONCLUSION: A pleasing proportion of projects funded by PHRDC in 1993 generated peer-reviewed publications and provided research training. Recipients perceive their research has influenced policy and practice. Recipients' views about strategies to increase funding for public health research are consistent with current reforms within the NHMRC. Policy makers emerge as a key target for training in research transfer.