Lack of effect of tart cherry concentrate dose on serum urate in people with gout.

OBJECTIVES: Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. METHODS: Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. RESULTS: Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. CONCLUSION: Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).

A Pilot Randomized Controlled Double-Blind Trial of High- Versus Low-Dose Weekly Folic Acid in People With Rheumatoid Arthritis Receiving Methotrexate.

BACKGROUND/OBJECTIVE: The aim of this study was to determine whether reducing the dose of supplemental folic acid used in conjunction with methotrexate (MTX) therapy in people with active rheumatoid arthritis (RA) improved disease control and/or increased MTX-related adverse effects. METHODS: A randomized double-blind randomized controlled trial comparing 5 mg/wk and 0.8 mg/wk folic acid was undertaken. Rheumatoid arthritis patients on MTX for 3 months or more at a stable dose for 1 month or more were recruited. All participants had DAS28 of 3.2 or greater or required a change in therapy determined by the treating clinician. Disease activity, full blood count, liver function tests, red blood cell (RBC) folate, and RBC MTX polyglutamates were assessed at weeks 0, 4, 8, 16, and 24 along with reports of adverse events. RESULTS: Forty participants were recruited. The mean (SD) change in RBC folate between week 0 and 24 was +87.9 (57.4) nmol/L in the high-dose group and -113.3 (65.7) nmol/L in the low-dose group (p < 0.05). There was no significant difference in the change in DAS28 between the high- and low-dose groups at 24 weeks (-0.13 [95% confidence interval, -0.69 to 0.43] vs -0.25 [-0.87 to 0.37], respectively [p = 0.78]). There was no significant difference in MTX-related adverse effects between the 2 groups. CONCLUSIONS: A reduction in RBC folate secondary to reduction in folic acid dose was not associated with a change in RA disease activity or MTX-related adverse effects. The prevention of MTX-related adverse effects remains the primary reason for coprescribing folic acid with MTX. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR12610000739011).

Assessing and managing multiple risks in a changing world-The Roskilde recommendations.

Roskilde University (Denmark) hosted a November 2015 workshop, Environmental Risk-Assessing and Managing Multiple Risks in a Changing World. This Focus article presents the consensus recommendations of 30 attendees from 9 countries regarding implementation of a common currency (ecosystem services) for holistic environmental risk assessment and management; improvements to risk assessment and management in a complex, human-modified, and changing world; appropriate development of protection goals in a 2-stage process; dealing with societal issues; risk-management information needs; conducting risk assessment of risk management; and development of adaptive and flexible regulatory systems. The authors encourage both cross-disciplinary and interdisciplinary approaches to address their 10 recommendations: 1) adopt ecosystem services as a common currency for risk assessment and management; 2) consider cumulative stressors (chemical and nonchemical) and determine which dominate to best manage and restore ecosystem services; 3) fully integrate risk managers and communities of interest into the risk-assessment process; 4) fully integrate risk assessors and communities of interest into the risk-management process; 5) consider socioeconomics and increased transparency in both risk assessment and risk management; 6) recognize the ethical rights of humans and ecosystems to an adequate level of protection; 7) determine relevant reference conditions and the proper ecological context for assessments in human-modified systems; 8) assess risks and benefits to humans and the ecosystem and consider unintended consequences of management actions; 9) avoid excessive conservatism or possible underprotection resulting from sole reliance on binary, numerical benchmarks; and 10) develop adaptive risk-management and regulatory goals based on ranges of uncertainty. Environ Toxicol Chem 2017;36:7-16. © 2016 SETAC.

The simulated early learning of cervical spine manipulation technique utilising mannequins.

BACKGROUND: Trivial pain or minor soreness commonly follows neck manipulation and has been estimated at one in three treatments. In addition, rare catastrophic events can occur. Some of these incidents have been ascribed to poor technique where the neck is rotated too far. The aims of this study were to design an instrument to measure competency of neck manipulation in beginning students when using a simulation mannequin, and then examine the suitability of using a simulation mannequin to teach the early psychomotor skills for neck chiropractic manipulative therapy. METHODS: We developed an initial set of questionnaire items and then used an expert panel to assess an instrument for neck manipulation competency among chiropractic students. The study sample comprised all 41 fourth year 2014 chiropractic students at Murdoch University. Students were randomly allocated into either a usual learning or mannequin group. All participants crossed over to undertake the alternative learning method after four weeks. A chi-square test was used to examine differences between groups in the proportion of students achieving an overall pass mark at baseline, four weeks, and eight weeks. RESULTS: This study was conducted between January and March 2014. We successfully developed an instrument of measurement to assess neck manipulation competency in chiropractic students. We then randomised 41 participants to first undertake either "usual learning" (n = 19) or "mannequin learning" (n = 22) for early neck manipulation training. There were no significant differences between groups in the overall pass rate at baseline (χ(2) = 0.10, p = 0.75), four weeks (χ(2) = 0.40, p = 0.53), and eight weeks (χ(2) = 0.07, p = 0.79). CONCLUSIONS: This study demonstrates that the use of a mannequin does not affect the manipulation competency grades of early learning students at short term follow up. Our findings have potentially important safety implications as the results indicate that students could initially gain competence in neck manipulation by using mannequins before proceeding to perform neck manipulation on each other.

Emphasis on various subtopics in the anatomy curriculum for chiropractic training: An international survey of chiropractors and anatomists.

OBJECTIVE: The aim of this study was to conduct an international survey of the perceived optimal level of anatomy teaching from anatomy academics and practicing chiropractors. We hypothesized that the optimum level of anatomical understanding for chiropractic students does not differ between the anatomists teaching the students and practicing chiropractors. METHODS: The opinion of anatomists teaching in a chiropractic course (n = 16) was compared to practicing chiropractors (n = 589). The students' level of understanding was based on the revised Bloom's taxonomy for 16 different curriculum areas. Anatomists were recruited by contacting the accredited chiropractic courses worldwide. Snowball sampling was used for the practicing chiropractors. Independent-samples Mann-Whitney U tests were used to compare the results of anatomists and chiropractors. RESULTS: Opinions differed between anatomists and chiropractors on 9 out of the 16 questions. Where opinions differed, chiropractors recommended a higher standard of anatomical knowledge. The level suggested by chiropractors for these curriculum areas is equal to the "evaluating" level where chiropractic students can remember, understand, apply, and analyze anatomical knowledge to be able to justify a clinical decision. CONCLUSION: Compared to anatomists working in chiropractic programs, chiropractors suggest a higher standard of anatomy be taught to undergraduates. Collaboration between chiropractors and anatomists would likely be beneficial in creating or modifying anatomy curricula for chiropractic students.

Comparison of two plasma urate assays in patients receiving vitamin C supplementation.

The aim of this study was to compare plasma urate (PU) concentrations using two different assays in patients receiving vitamin C supplementation. PU was measured using two routinely available enzymatic uricase methods: (1) uric acid plus method (ascorbate oxidase assay), and (2) uric acid method (non-ascorbate oxidase assay). Twenty patients receiving allopurinol were randomised to an increase in allopurinol dose or commence vitamin C 500  mg/d on a 1:1 ratio. Twenty patients not receiving allopurinol were randomised to start allopurinol or vitamin C 500  mg/d on a 1:1 ratio. Trough fasting samples for plasma ascorbate and urate were measured weekly until week 8. There was no significant difference in the mean PU measured by the two assays. In patients not receiving supplemental vitamin C the mean PU concentrations were identical for both assays. For patients receiving supplemental vitamin C the mean PU concentrations for the ascorbate oxidase assay was 0.525  mmol/L (SE 0.034) and for the non-ascorbate oxidase assay 0.510  mmol/L (SE 0.033), p = 0.079.There is a small non-significant difference in measured PU in patients receiving supplemental vitamin C between the two assays. The assay which does not include ascorbate oxidase results in consistently lower PU concentrations compared to the assay which includes ascorbate oxidase.

Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout: a pilot randomized controlled trial.

OBJECTIVE: Studies in human volunteers have shown that vitamin C reduces serum urate (SU) levels. The aim of this study was to determine the effects of vitamin C on SU levels in patients with gout. METHODS: Patients with gout and an SU level >0.36 mmoles/liter (6 mg/dl) were recruited. Twenty patients already taking allopurinol were randomized to receive an increase in the dose of allopurinol or to commence taking vitamin C (500 mg/day). Twenty patients who had not been taking allopurinol were randomized to start receiving either allopurinol (up to 100 mg/day) or vitamin C (500 mg/day). Levels of plasma ascorbate, creatinine, and SU were measured on day 0 and week 8. RESULTS: There was no significant difference in the baseline SU level or estimated glomerular filtration rate (eGFR) between those who received vitamin C and those who did not (for SU, mean ± SEM 0.50 ± 0.11 mmoles/liter [8.4 ± 1.8 mg/dl] versus 0.50 ± 0.09 mmoles/liter [8.4 ± 1.5 mg/dl]; for eGFR, mean ± SEM 65.5 ± 3.5 ml/minute/1.73 m(2) versus 67.9 ± 4.6 ml/minute/1.73 m(2) ). Among the randomized patients, 30% in the vitamin C group and 25% in the no vitamin C control group were receiving diuretics. In the patients receiving vitamin C, there was a significant increase between day 0 and week 8 in the plasma ascorbate level. The reduction in SU level over 8 weeks was significantly less in those patients receiving vitamin C compared to those who started or increased the dose of allopurinol (mean reduction 0.014 mmoles/liter [0.23 mg/dl] versus 0.118 mmoles/liter [1.9 mg/dl]; P < 0.001). CONCLUSION: A modest dosage of vitamin C (500 mg/day) for 8 weeks had no clinically significant urate-lowering effects in patients with gout, despite the fact that plasma ascorbate levels increased. These results differ from previous findings in healthy control subjects with hyperuricemia. The uricosuric effect of modest-dose vitamin C appears to be small in patients with gout, when administered as monotherapy or in combination with allopurinol.

The importance of both potency and mechanism in dose-response analysis: an example from exposure of Pacific herring (Clupea pallasi) embryos to low concentrations of weathered crude oil.

This paper reanalyzes data from an earlier study that used effluents from oiled-gravel columns to assess the toxicity of aqueous fractions of weathered crude oil to Pacific herring embryos and larvae. This reanalysis has implications for future similar investigations, including the observance of two distinct dose-response curves for lethal and sublethal endpoints for different exposures in the same experiment, and the need to consider both potency and slope of dose-response curves for components of a toxicant mixture that shows potentially different toxicity mechanisms/causation. Contrary to conclusions of the original study, the aqueous concentration data cannot support the hypothesis that polycyclic aromatic hydrocarbons (PAHs) were the sole cause of toxicity and that oil toxicity increased with weathering. Confounding issues associated with the oiled gravel columns include changes in the concentration and composition of chemicals in exposure water, which interfere with the production of reliable and reproducible results relevant to the field.

Evaluating the aquatic toxicity of complex organic chemical mixtures: lessons learned from polycyclic aromatic hydrocarbon and petroleum hydrocarbon case studies.

Experimental designs for evaluating complex mixture toxicity in aquatic environments can be highly variable and, if not appropriate, can produce and have produced data that are difficult or impossible to interpret accurately. We build on and synthesize recent critical reviews of mixture toxicity using lessons learned from 4 case studies, ranging from binary to more complex mixtures of primarily polycyclic aromatic hydrocarbons and petroleum hydrocarbons, to provide guidance for evaluating the aquatic toxicity of complex mixtures of organic chemicals. Two fundamental requirements include establishing a dose-response relationship and determining the causative agent (or agents) of any observed toxicity. Meeting these 2 requirements involves ensuring appropriate exposure conditions and measurement endpoints, considering modifying factors (e.g., test conditions, test organism life stages and feeding behavior, chemical transformations, mixture dilutions, sorbing phases), and correctly interpreting dose-response relationships. Specific recommendations are provided.

Developmental toxicity of selenium to Dolly Varden char (Salvelinus malma).

Gametes were collected from Dolly Varden char (Salvelinus malma) from waterbodies in a region exposed to mining-related selenium (Se) releases in British Columbia, Canada. Fertilized eggs were incubated in a laboratory and deformities were assessed on newly-hatched alevins using a graduated severity index. No effects were observed on egg or alevin survival or larval weight across the studied exposure range of 5.4 to 66 mg/kg dry weight in egg. Length of some larvae was reduced at the highest egg Se concentrations and a clear residue-response relationship was observed for larval deformity. The egg concentration corresponding to a 10% increase in the frequency of deformity (EC10) was 54 mg/kg dry weight, which is substantially higher than reported for other cold-water fish species.

Is selenium a global contaminant of potential concern?

Selenium is not a new contaminant, but its environmental presence and significance are only now being evaluated. It has been and will continue to be "discovered" in a variety of water bodies generally due to improved analytical chemical detection limits. It has the potential to cause deleterious effects on aquatic life at environmentally relevant concentrations, and there is no definitive regulatory standard for chronic effects. The US Environmental Protection Agency (2004) has recognized the need for a tissue Guideline/criterion, but has not yet finalized such a value. A SETA Pellston Workshop (Pensacola, FL, USA, February 23-28, 2009) has determined the state-of-the-science related to ecological assessment of Se in the aquatic environment. The Workshop Executive Summary will shortly be forthcoming followed by a more detailed book published by SETAC Press. However, this workshop was constrained by the areas of the world (see above) where Se has been recognized as a contaminant of potential concern and for which information is available. Thus, by way of this Learned Discourse I solicit information from readers as to whether Se is present at concentrations of concern in other parts of the world than North America, Australia, and New Zealand and, if so, "So what?" (i. e., are there adverse effects to individuals and/or impacts to populations of fish, water birds, and/or amphibians?).

A conceptual selenium management model.

We describe herein a conceptual selenium (Se) management model, directed toward coal mining in western Canada, but which can be applied to other coal mines and, with appropriate modification, to other industrial sources of Se to aquatic and terrestrial environments. This conceptual model provides a transparent means to integrate and synthesize existing information that can be used to provide an adaptive approach for managing ecological exposures and associated risk. It is particularly useful for visualizing and subsequently developing management interventions for Se control and risk reduction. The model provides a structured process by which critical information needs can be identified and addressed. It effectively provides the foundation for making management decisions related to Se discharges to aquatic and terrestrial environments by showing interrelationships of the various media and receptors as well as primary sources, release mechanisms, secondary sources, and exposure pathways.

Effects of an oil spill on the regrowth of emergent vegetation in a northern Alberta Lake.

Following a train derailment in August 2005, Wabamun Lake (Alberta, Canada) was exposed to approximately 149,500 L of bunker "C" oil, much of which became entrained in the abundant Schoenoplectus tabernaemontani (= Scirpus validus) beds in the eastern basin of the lake. We assessed the regrowth of emergent macrophytes during the subsequent two growing seasons. Postspill measures of productivity, including transect length, total cover, and biomass were within the variability of prespill data collected in 2001, with the exception of a few specific areas in which biomass appeared to be affected. We conclude that exposure to oil during the late growing season in August 2005 and through the winter senescent period and regrowth in the summers of 2006 and 2007 did not cause large-scale changes to S. tabernaemontani communities. Physical factors such as cleanup activities and vegetation management appeared to be responsible for the reduced regrowth observed at some locations. Few previous studies have been published on the effects of oil spilled into freshwater on macrophyte communities; thus, the results of this study are expected to provide useful information for the assessment of future freshwater oil spills.

The need for adequate quality assurance/quality control measures for selenium larval deformity assessments: implications for tissue residue guidelines.

Assessing the frequency and severity of larval fish deformities is a subjective exercise that is subject to considerable parameter uncertainty unless appropriate quality assurance/quality control (QA/QC) measures are incorporated. This issue has received limited attention in the literature. Only one study was identified that contained adequate data to evaluate the reproducibility of larval deformity data. Parameter uncertainty was substantially larger than expected. There was poor reproducibility between observers for nearly all types and magnitudes of deformities, and there were particularly large differences in how mild deformities were assessed. The reproducibility of the edema endpoint was the poorest of the 4 types of deformity evaluated. Specific recommendations for improving the QA/QC aspects of larval deformity assessments include blind and nonsequential labeling; explicit effort on the development and application of an a priori framework; internal QC checks to quantify the influence of sample preservatives, observer drift, or multiple observers; and an external QC check of a minimum of 10% of all larval fish. Future selenium reproductive studies should include an explicit uncertainty analysis and disclose raw deformity data to facilitate recalculation of tissue residue guidelines as the science in this area advances.

What is an appropriate level of protection? An example considering selenium exposures by aquatic birds.

Evaluating population-level risks to ecological receptors or developing toxicity thresholds intended to be protective of a population requires a population model to truly understand possible chemical-related impacts to the population of interest. For various reasons (e.g., lack of training in the application of population models to ecotoxicological questions), we often use laboratory-based (more common) or field-based (less common) toxicity data to develop a toxicity threshold that is assumed to be protective of population-level effects. Under this latter approach, an appropriate level of protection against exposure should focus on protecting the viability and productivity of populations of organisms, that is, maintaining approximately the same density of individuals over time. The EC values can be used to set technically defensible levels of protection, with the appropriate effect level being determined on the basis of data- and site-specific considerations and dose-response relationships that are amenable for use as inputs in population models. Even without the use of predictive population models, the ECO10 or EC20 are commonly used values in risk assessment or criteria development with the assumption of adequate protection of populations. In the Se example presented here, there is strong evidence that egg hatchability is the critical toxicity endpoint for birds based on dietary organic Se exposures and that mallards are a sensitive bird species. These factors support that the dietary Se EC10 derived by Ohlendorf (2003) is sufficiently low to not have any measurable effects on aquatic birds in the field. Further, effect levels below the EC10 are likely to be statistically indistinguishable from the controls in most situations (as it was for Se in this example), and, for Se and other naturally occurring elements, it is not unusual for lower EC values to approach or fall below background levels at a site. A determination as to whether higher EC values would also provide an adequate level of protection could be made by appropriate population modeling.

In situ experimental assessment of lake whitefish development following a freshwater oil spill.

Wabamun Lake (Alberta, Canada) has been subject to ongoing contamination with polycyclic aromatic hydrocarbons (PAHs) from multiple sources for decades and in August 2005 was exposed to ca. 149 500 L of bunker C oil following a train derailment. We compared the pattern, frequency, and severity of deformity in larvae of lake whitefish (Coregonus clupeaformis) incubated in situ in areas of Wabamun Lake exposed only to "background" PAH contamination and in areas additionally exposed to PAHs from the oil. All sites in the lake (including reference areas) showed incidences of deformity higher than are typically observed in laboratory studies. A small number of oil-exposed sites showed higher incidences of some teratogenic deformities and a tendency to exhibit deformities of higher severity than sites not exposed to oil. The frequency of moderate to severe deformities in 8 of 16 classes was correlated with PAH exposure. Nonmetric multivariate ordination of deformity data revealed a general pattern of increasing incidence and severity of several skeletal (lordosis, scoliosis) and craniofacial (ocular, jaw) deformities at sites with relatively high exposure to oil-derived PAHs. A simultaneous consideration of incidence, severity, and pattern of deformity enabled us to detect a consistent (overall approximately 5% above background) response to the oil despite high variability and high background deformity rates in this historically contaminated environment.

A control chart approach to monitoring and communicating trends in tissue selenium concentrations.

A primary aim of monitoring programs is to determine changes relative to background conditions, which typically represent a distribution of values, not a single value, and which may be elevated naturally. Graphical inspection of the statistical distribution of background and subsequent data provides the best means to determine changes over time and the relative significance of those changes based on both their magnitude and trajectory. The control chart approach commonly used in laboratory and product testing is a useful tool that allows for such determinations in a manner that is transparent to both scientists and nonscientists. This approach can be used both with true baseline (i.e., pre-development) data and with operational baseline (i.e., post-development) data and is particularly relevant for monitoring selenium (Se) tissue concentrations.

Selenium toxicity to invertebrates: will proposed thresholds for toxicity to fish and birds also protect their prey?

Efforts to manage the environmental risks of selenium (Se) in freshwater ecosystems have focused primarily on fish and birds, with invertebrates most often considered only as dietary sources of Se to higher trophic levels. Relatively little attention has been given to the risk of Se toxicity to invertebrates. Based on a review of 156 aqueous, dietary, or internal Se concentrations associated with toxic effects in 29 macroinvertebrate species, we found that water concentrations associated with acute lethality varied > 1000-fold among taxa, whereas toxic dietary concentrations varied approximately 100-fold and toxic internal concentrations varied about 30-fold. Sublethal effects occurred at approximately 10-fold lower concentrations than lethality. Sublethal effects occurred at 1-30 microg Se/g dry weight in invertebrate tissue, a range that encompasses proposed dietary thresholds for toxicity to fish and water birds, suggesting that Se may cause toxic effects in some invertebrate species at concentrations considered to be "safe" for the organisms consuming them.