Researchers’ attitudes to the 3Rs - An upturned hierarchy?

Animal use in biomedical research is generally justified by its potential benefits to the health of humans, or other animals, or the environment. However, ethical acceptability also requires scientists to limit harm to animals in their research. Training in laboratory animal science (LAS) helps scientists to do this by promoting best practice and the 3Rs. This study evaluated scientists’ awareness and application of the 3Rs, and their approach to other ethical issues in animal research. It was based on an online survey of participants in LAS courses held in eight venues in four European countries: Portugal (Porto, Braga), Germany (Munich, Heidelberg), Switzerland (Basel, Lausanne, Zurich), and Denmark (Copenhagen). The survey questions were designed to assess general attitudes to animal use in biomedical research, Replacement alternatives, Reduction and Refinement conflicts, and harm-benefit analysis. The survey was conducted twice: immediately before the course (‘BC’, N = 310) and as a follow-up six months after the course (‘AC’, N = 127). While courses do appear to raise awareness of the 3Rs, they had no measurable effect on the existing low level of belief that animal experimentation can be fully replaced by non-animal methods. Most researchers acknowledged ethical issues with their work and reported that they discussed these with their peers. The level of an animal’s welfare, and especially the prevention of pain, was regarded as the most pressing ethical issue, and as more important than the number of animals used or the use of animals as such. Refinement was considered more feasible than Replacement, as well as more urgent, and was also favoured over Reduction. Respondents in the survey reversed the ‘hierarchy’ of the 3Rs proposed by their architects, Russell and Burch, prioritizing Refinement over Reduction, and Reduction over Replacement. This ordering may conflict with the expectations of the public and regulators.</div

Current debates in urban theory: a critical assessment

Urban studies today is marked by many active debates. In an earlier paper, we addressed some of these debates by proposing a foundational concept of urbanization and urban form as a way of identifying a common language for urban research. In the present paper we provide a brief recapitulation of that framework. We then use this preliminary material as background to a critique of three currently influential versions of urban analysis, namely, postcolonial urban theory, assemblage theoretic approaches, and planetary urbanism. We evaluate each of these versions in turn and find them seriously wanting as statements about urban realities. We criticize (a) postcolonial urban theory for its particularism and its insistence on the provincialization of knowledge, (b) assemblage theoretic approaches for their indeterminacy and eclecticism, and (c) planetary urbanism for its radical devaluation of the forces of agglomeration and nodality in urban-economic geography

Systematic Reviews of Animal Experiments Demonstrate Poor Human Clinical and Toxicological Utility

The assumption that animal models are reasonably predictive of human outcomes provides the basis for their widespread use in toxicity testing and in biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, the comprehensive Scopus biomedical bibliographic databases were searched for published systematic reviews of the human clinical or toxicological utility of animal experiments. In 20 reviews in which clinical utility was examined, the authors concluded that animal models were either significantly useful in contributing to the development of clinical interventions, or were substantially consistent with clinical outcomes, in only two cases, one of which was contentious. These included reviews of the clinical utility of experiments expected by ethics committees to lead to medical advances, of highly-cited experiments published in major journals, and of chimpanzee experiments — those involving the species considered most likely to be predictive of human outcomes. Seven additional reviews failed to clearly demonstrate utility in predicting human toxicological outcomes, such as carcinogenicity and teratogenicity. Consequently, animal data may not generally be assumed to be substantially useful for these purposes. Possible causes include interspecies differences, the distortion of outcomes arising from experimental environments and protocols, and the poor methodological quality of many animal experiments, which was evident in at least 11 reviews. No reviews existed in which the majority of animal experiments were of good methodological quality. Whilst the effects of some of these problems might be minimised with concerted effort (given their widespread prevalence), the limitations resulting from interspecies differences are likely to be technically and theoretically impossible to overcome. Non-animal models are generally required to pass formal scientific validation prior to their regulatory acceptance. In contrast, animal models are simply assumed to be predictive of human outcomes. These results demonstrate the invalidity of such assumptions. The consistent application of formal validation studies to all test models is clearly warranted, regardless of their animal, non-animal, historical, contemporary or possible future status. Likely benefits would include, the greater selection of models truly predictive of human outcomes, increased safety of people exposed to chemicals that have passed toxicity tests, increased efficiency during the development of human pharmaceuticals and other therapeutic interventions, and decreased wastage of animal, personnel and financial resources. The poor human clinical and toxicological utility of most animal models for which data exists, in conjunction with their generally substantial animal welfare and economic costs, justify a ban on animal models lacking scientific data clearly establishing their human predictivity or utility

Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium

Background: Delirium in patients with hip fractures lead to higher morbidity and mortality. Prevention in high-risk patients by prescribing low dose haloperidol is currently under investigation. Methods. This prospective cohort surveillance assessed hip fracture patients for risk of developing a delirium with the Risk Model for Delirium (RD) score. High-risk patients (score ≥5 points) were treated with a prophylactic low-dose of haloperidol according to hospital protocol. Primary outcome was delirium incidence. Secondary outcomes were differences between high- and low-risk patients in delirium, length of stay (LOS), return to pre-fracture living situation and mortality. Logistic regression analysis was performed with age, ASA-classification, known dementia, having a partner, type of fracture, institutional residence and psychotropic drug use as possible confounders. Results: 445 hip fracture patients aged 65 years and older were admitted from January 2008 to December 2009. The RD-score was completed in 378 patients, 173 (45.8%) high-risk patients were treated with prophylactic medication. Sensitivity was 71.6%, specificity 63.8% and the negative predictive value (NPV) of a score < 5 was 85.9%. Delirium incidence (27.0%) was not significantly different compared to 2007 (27.8%) 2006 (23.9%) and 2005 (29.0%) prior to implementation of the RD- protocol. Logistic regression analysis showed that high-risk patients did have a significant higher delirium incidence (42.2% vs. 14.1%, OR 4.1, CI 2.43-7.02). They were more likely to be residing at an alternative living situation after 3 months (62.3% vs. 17.0%, OR 6.57, CI 3.23-13.37) and less likely to be discharged from hospital before 10 days (34.9% vs. 55.9%, OR 1.63, CI 1.03-2.59). Significant independent risk factors for a delirium were a RD-score 5 (OR 4.13, CI 2.43-7.02), male gender (OR 1.93, CI 0.99-1.07) and age (OR 1.03, CI 0.99-1.07). Conclusions: Introducing the delirium prevention protocol did not reduce delirium incidence. The RD-score did identify patients with a high risk to develop a delirium. This high-risk group had a longer LOS and returned to pre-fracture living situation less often. The NPV of a score < 5 was high, as it should be for a screening instrument. Concluding, the RD-score is a useful tool to identify patients with poorer outcome

Self-control enhancement in children:Ethical and conceptual aspects

Childhood self-control is currently receiving great scientific and public attention because it could predict much of adult’s life success and well-being. Specialized interventions based on findings in social psychology and neuroscience potentially enhance children’s capacity to exercise self-control. This perspective triggers hopes that self-control enhancement allows us to say good-bye for good to potentially unsafe psychopharmacological agents and electronic brain stimulants. This chapter provides an in-depth ethical analysis of pediatric self-control enhancement and points toward a series of serious conceptual and ethical concerns. First, it gives an overview of current psychological as well as neuroscientific research on self-control, and it presents longitudinal studies that emphasize the importance of childhood self-control for adult life success. Second, it critically discusses the concept of self-control presupposed in these approaches and points to crucial limitations. Going beyond an understanding of self-control as a sophisticated means of goal-achievement, i will argue for a comprehensive understanding that takes the inherent normativity of self-controlled behavior seriously. In that context, self-control enhancement appears as not necessarily desirable and occasionally even detrimental. Finally, this chapter questions the notion of childhood implicit in current research and how values typically put on this phase of life could get affected by self-control enhancement. I finish with an exploration of the conditions under which pediatric self-control enhancement is either impermissible, permissible, or maybe obligatory

Reversal of stress fibre formation by Nitric Oxide mediated RhoA inhibition leads to reduction in the height of preformed thrombi

Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation and inhibition. We hypothesised that Nitric oxide (NO), a platelet inhibitor, can modulate the actin cytoskeleton reversing platelet spreading, and therefore reduce the capability of thrombi to withstand a high shear environment. Our data demonstrates that GSNO, DEANONOate, and a PKG-activating cGMP analogue reversed stress fibre formation and increased actin nodule formation in adherent platelets. This effect is sGC dependent and independent of ADP and thromboxanes. Stress fibre formation is a RhoA dependent process and NO induced RhoA inhibition, however, it did not phosphorylate RhoA at ser188 in spread platelets. Interestingly NO and PGI2 synergise to reverse stress fibre formation at physiologically relevant concentrations. Analysis of high shear conditions indicated that platelets activated on fibrinogen, induced stress fibre formation, which was reversed by GSNO treatment. Furthermore, preformed thrombi on collagen post perfused with GSNO had a 30% reduction in thrombus height in comparison to the control. This study demonstrates that NO can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling excessive thrombosis

Motor Decline in Clinically Presymptomatic Spinocerebellar Ataxia Type 2 Gene Carriers

BACKGROUND: Motor deficits are a critical component of the clinical characteristics of patients with spinocerebellar ataxia type 2. However, there is no current information on the preclinical manifestation of those motor deficits in presymptomatic gene carriers. To further understand and characterize the onset of the clinical manifestation in this disease, we tested presymptomatic spinocerebellar ataxia type 2 gene carriers, and volunteers, in a task that evaluates their motor performance and their motor learning capabilities. METHODS AND FINDINGS: 28 presymptomatic spinocerebellar ataxia type 2 gene carriers and an equal number of control volunteers matched for age and gender participated in the study. Both groups were tested in a prism adaptation task known to be sensible to both motor performance and visuomotor learning deficits. Our results clearly show that although motor learning capabilities are intact, motor performance deficits are present even years before the clinical manifestation of the disease start. CONCLUSIONS: The results show a clear deficit in motor performance that can be detected years before the clinical onset of the disease. This motor performance deficit appears before any motor learning or clinical manifestations of the disease. These observations identify the performance coefficient as an objective and quantitative physiological biomarker that could be useful to assess the efficiency of different therapeutic agents

Swimming Exercise Prevents Fibrogenesis in Chronic Kidney Disease by Inhibiting the Myofibroblast Transdifferentiation

BACKGROUND: The renal function of chronic kidney disease (CKD) patients may be improved by a number of rehabilitative mechanisms. Swimming exercise training was supposed to be beneficial to its recovery. METHODOLOGY/PRINCIPAL FINDINGS: Doxorubicin-induced CKD (DRCKD) rat model was performed. Swimming training was programmed three days per week, 30 or 60 min per day for a total period of 11 weeks. Serum biochemical and pathological parameters were examined. In DRCKD, hyperlipidemia was observed. Active mesangial cell activation was evidenced by overexpression of PDGFR, P-PDGFR, MMP-2, MMP-9, α-SMA, and CD34 with a huge amount collagen deposition. Apparent myofibroblast transdifferentiation implicating fibrogenesis in the glomerular mesangium, glomerulonephritis and glomeruloscelorosis was observed with highly elevated proteinuria and urinary BUN excretion. The 60-min swimming exercise but not the 30 min equivalent rescued most of the symptoms. To quantify the effectiveness of exercise training, a physical parameter, i.e. "the strenuosity coefficient" or "the myokine releasing coefficient", was estimated to be 7.154 × 10(-3) pg/mL-J. CONCLUSIONS: The 60-min swimming exercise may ameliorate DRCKD by inhibiting the transdifferentiation of myofibroblasts in the glomerular mesangium. Moreover, rehabilitative exercise training to rescue CKD is a personalized remedy. Benefits depend on the duration and strength of exercise, and more importantly, on the individual physiological condition