The Dynamics of Sedimentary Systems and the Whimsicality of Policy Processes

Background, Aims, and Scope. Sediment management in coastal zones is taking place in high complex environments. Present management options do not have a sophisticated way of dealing with the actual complexity of the physical and the social systems and with the unpredictability that is inherent with these systems. Therefore, a new approach in both policy making and sediment management is needed that takes this complexity into account. The aim of this article is to explore the dynamics in social and natural systems and to draw the contours of this new approach for policy processes and sediment management that fits to the dynamics of the systems. Results and Discussion. The case studies show that chance events can occur in the biophysical and in the social system. In the three cases, players or actors in the decision process are left with the choice to adapt themselves to the occurring chance events or to refrain from any adaptive behaviour. Chance events can open up new possibilities by activating (new) actors and by coupling to new issues. If the situation is too locked-in (i.e. a stalemate) and is intentional on behalf of the actors, than the chance event will have no effect. T

Heterosexual interactions of pairs of laboratory-housed stumptail macaques (Macaca arctoides) under continuous observation with closed-circuit video recording

Female-male interaction of heterosexual pairs of stumptail macaques, housed together continuously, was studied 24 hr per day using closed-circuit video recording. Two pairs were studied for approximately 2 months each. Although no generalizations can be made from such a small sample, no aspect of behavioral interaction varied significantly with the stage of the menstrual cycle of the female partner. Copulation occurred regularly but only during the daylight hours. Both pairs showed several peak ejaculation days (5-21 ejaculations/day), which were distributed throughout the entire menstrual cycle. In general, the highest number of ejaculations was observed to occur when the animals were put together either for the first time or following a separation of a few days. In one pair the female became pregnant, and from the fifth week of pregnancy onward there was a gradual increase in male aggression, coinciding with a decrease in male sexual and grooming behavior. In a second study eight different pairs were observed during the first day together and male copulatory behavior was studied. Two patterns of copulatory behavior could be discerned: pairs displaying a high number of ejaculations (19-38) and pairs displaying a low number of ejaculations (4-8). With regard to the interejaculatory interval (IEI), the male stumptail appeared to be unique. In contrast to what has been reported for other mammals, i.e., a steady increase in IEI with subsequent ejaculations, the stumptail showed increasing IEIs only during the first three to four, as well as between the last, ejaculations; in between, the IEI remained relatively constant. The maximum number of consecutive ejaculations observed was 38, displayed during a 10-hr time period (mean (± SEM)IEI, 12.9 ± 3.5 min)

Heat shock protein expression analysis in canine osteosarcoma reveals HSP60 as a potentially relevant therapeutic target

Heat shock proteins (HSP) are highly conserved across eukaryotic and prokaryotic species. These proteins play a role in response to cellular stressors, protecting cells from damage and facilitating recovery. In tumor cells, HSPs can have cytoprotective effects and interfere with apoptotic cascades. This study was performed to assess the prognostic and predictive values of the gene expression of HSP family members in canine osteosarcoma (OS) and their potential for targeted therapy. Gene expressions for HSP were assessed using quantitative PCR (qPCR) on 58 snap-frozen primary canine OS tumors and related to clinic-pathological parameters. A significant increased expression of HSP60 was found in relation to shorter overall survival and an osteoblastic phenotype. Therefore, the function of HSP60 was investigated in more detail. Immunohistochemical analysis revealed heterogeneous staining for HSP60 in tumors. The highest immunoreactivity was found in tumors of short surviving dogs. Next HSP expression was shown in a variety of canine and human OS cell lines by qPCR and Western blot. In two highly metastatic cell lines HSP60 expression was silenced using siRNA resulting in decreased cell proliferation and induction of apoptosis in both cell lines. It is concluded that overexpression of HSP60 is associated with a poor prognosis of OS and should be evaluated as a new target for therapy

Genotoxic mixtures and dissimilar action: Concepts for prediction and assessment

This article has been made available through the Brunel Open Access Publishing Fund. This article is distributed under the terms of the creative commons Attribution license which permits any use, distribution, and reproduction in any medium, provided the original author(s)and the source are credited.Combinations of genotoxic agents have frequently been assessed without clear assumptions regarding their expected (additive) mixture effects, often leading to claims of synergisms that might in fact be compatible with additivity. We have shown earlier that the combined effects of chemicals, which induce micronuclei (MN) in the cytokinesis-block micronucleus assay in Chinese hamster ovary-K1 cells by a similar mechanism, were additive according to the concept of concentration addition (CA). Here, we extended these studies and investigated for the first time whether valid additivity expectations can be formulated for MN-inducing chemicals that operate through a variety of mechanisms, including aneugens and clastogens (DNA cross-linkers, topoisomerase II inhibitors, minor groove binders). We expected that their effects should follow the additivity principles of independent action (IA). With two mixtures, one composed of various aneugens (colchicine, flubendazole, vinblastine sulphate, griseofulvin, paclitaxel), and another composed of aneugens and clastogens (flubendazole, doxorubicin, etoposide, melphalan and mitomycin C), we observed mixture effects that fell between the additivity predictions derived from CA and IA. We achieved better agreement between observation and prediction by grouping the chemicals into common assessment groups and using hybrid CA/IA prediction models. The combined effects of four dissimilarly acting compounds (flubendazole, paclitaxel, doxorubicin and melphalan) also fell within CA and IA. Two binary mixtures (flubendazole/paclitaxel and flubendazole/doxorubicin) showed effects in reasonable agreement with IA additivity. Our studies provide a systematic basis for the investigation of mixtures that affect endpoints of relevance to genotoxicity and show that their effects are largely additive.UK Food Standards Agenc

SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male

Genetic predispositions moderate the effectiveness of tobacco excise taxes.

BACKGROUND: Tobacco consumption is one of the leading causes of preventable death. In this study, we analyze whether someone's genetic predisposition to smoking moderates the response to tobacco excise taxes. METHODS: We interact polygenic scores for smoking behavior with state-level tobacco excise taxes in longitudinal data (1992-2016) from the US Health and Retirement Study (N = 12,058). RESULTS: Someone's genetic propensity to smoking moderates the effect of tobacco excise taxes on smoking behavior along the extensive margin (smoking vs. not smoking) and the intensive margin (the amount of tobacco consumed). In our analysis sample, we do not find a significant gene-environment interaction effect on smoking cessation. CONCLUSIONS: When tobacco excise taxes are relatively high, those with a high genetic predisposition to smoking are less likely (i) to smoke, and (ii) to smoke heavily. While tobacco excise taxes have been effective in reducing smoking, the gene-environment interaction effects we observe in our sample suggest that policy makers could benefit from taking into account the moderating role of genes in the design of future tobacco control policies

A phase II dose-ranging study of mirabegron in patients with overactive bladder

Introduction and hypothesis Mirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder. Methods Patients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n=928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume. Results Mirabegron 25, 50, 100, and 200 mg resulted in dosedependent reductions (improvements) from baseline to end-oftreatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p≤0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p<0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events. Conclusions The favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program

Dispelling urban myths about default uncertainty factors in chemical risk assessment - Sufficient protection against mixture effects?

© 2013 Martin et al.; licensee BioMed Central LtdThis article has been made available through the Brunel Open Access Publishing Fund.Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. © 2013 Martin et al.; licensee BioMed Central Ltd.Oak Foundatio