Semi-quantitative analysis of protease activity

Semi-quantitative analysis of protease activit

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

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

Topography and malaria transmission heterogeneity in western Kenya highlands: prospects for focal vector control

BACKGROUND: Recent resurgence of malaria in the highlands of Western Kenya has called for a more comprehensive understanding of the previously neglected complex highland vector ecology. Besides other drivers of malaria epidemiology, topography is likely to have a major effect on spatial vector and parasite distribution. The aim of this study was to determine the effects of topography on malaria spatial vector distribution and parasite prevalence. METHODOLOGY: Indoor resting adult malaria vectors and blood parasites were collected in three villages along a 4 km transect originating from the valley bottom and ending at the hilltop for 13 months. Members of the Anopheles gambiae complex were identified by PCR. Blood parasites were collected from children 6–13 years old and densities categorized by site of home location and age of the children. RESULTS: Ninety eight percent (98%) of An. gambiae s.s. and (99%) Anopheles funestus were collected in houses located at the edge of the valley bottom, whereas 1% of An. gambiae s.s. were collected at mid hill and at the hilltop respectively. No An. funestus were collected at the hilltop. Malaria prevalence was 68% at the valley bottom, 40.2% at mid hill and 26.7% at the hilltop. Children aged six years and living at the edge of the valley bottom had an annual geometric mean number of 66.1 trophozoites for every 200 white blood cells, while those living at mid-hill had a mean of 84.8, and those living at hilltop had 199.5 trophozoites. CONCLUSION: Malaria transmission in this area is mainly confined to the valley bottom. Effective vector control could be targeted at the foci. However, the few vectors observed at mid-hill maintained a relatively high prevalence rate. The higher variability in blood parasite densities and their low correlation with age in children living at the hilltop suggests a lower stability of transmission than at the mid-hill and valley bottom

Patient-directed self-management of pain (PaDSMaP) compared to treatment as usual following total knee replacement; a randomised controlled trial

Background Self-administration of medicines by patients whilst in hospital is being increasingly promoted despite little evidence to show the risks and benefits. Pain control after total knee replacement (TKR) is known to be poor. The aim of the study was to determine if patients operated on with a TKR who self-medicate their oral analgesics in the immediate post-operative period have better pain control than those who receive their pain control by nurse-led drug rounds (Treatment as Usual (TAU)). Methods A prospective, parallel design, open-label, randomised controlled trial comparing pain control in patient-directed self-management of pain (PaDSMaP) with nurse control of oral analgesia (TAU) after a TKR. Between July 2011 and March 2013, 144 self-medicating adults were recruited at a secondary care teaching hospital in the UK. TAU patients (n = 71) were given medications by a nurse after their TKR. PaDSMaP patients (n = 73) took oral medications for analgesia and co-morbidities after two 20 min training sessions reinforced with four booklets. Primary outcome was pain (100 mm visual analogue scale (VAS)) at 3 days following TKR surgery or at discharge (whichever came soonest). Seven patients did not undergo surgery for reasons unrelated to the study and were excluded from the intention-to-treat (ITT) analysis. Results ITT analysis did not detect any significant differences between the two groups’ pain scores. A per protocol (but underpowered) analysis of the 60% of patients able to self-medicate found reduced pain compared to the TAU group at day 3/discharge, (VAS -9.9 mm, 95% CI -18.7, − 1.1). One patient in the self-medicating group over-medicated but suffered no harm. Conclusion Self-medicating patients did not have better (lower) pain scores compared to the nurse-managed patients following TKR. This cohort of patients were elderly with multiple co-morbidities and may not be the ideal target group for self-medication

The Polycentric State: New Spaces of Empowerment and Engagement?

New Labour claims to have radically reformed territorial governance structures in the UK by devolving political power to the Celtic nations and London, begetting the most enduring legacy of the first Blair government. More recently it has sought to extend its devolution agenda by embracing city-regionalism and the new localism, ostensibly to create new spaces of empowerment and engagement. But devolution is not the whole story of New Labour’s attitude to power. On the contrary, this article argues that New Labour is a modern Janus because its commitment to devolving power, so clear in principle, is more equivocal in practice. Drawing on these three devolution narratives, the article concludes by assessing the implications for the current debate about relational versus territorial readings of place politics

Sensitivity of Anopheles gambiae population dynamics to meteo-hydrological variability: a mechanistic approach

<p>Abstract</p> <p>Background</p> <p>Mechanistic models play an important role in many biological disciplines, and they can effectively contribute to evaluate the spatial-temporal evolution of mosquito populations, in the light of the increasing knowledge of the crucial driving role on vector dynamics played by meteo-climatic features as well as other physical-biological characteristics of the landscape.</p> <p>Methods</p> <p>In malaria eco-epidemiology landscape components (atmosphere, water bodies, land use) interact with the epidemiological system (interacting populations of vector, human, and parasite). In the background of the eco-epidemiological approach, a mosquito population model is here proposed to evaluate the sensitivity of <it>An. gambiae </it>s.s. population to some peculiar thermal-pluviometric scenarios. The scenarios are obtained perturbing meteorological time series data referred to four Kenyan sites (Nairobi, Nyabondo, Kibwesi, and Malindi) representing four different eco-epidemiological settings.</p> <p>Results</p> <p>Simulations highlight a strong dependence of mosquito population abundance on temperature variation with well-defined site-specific patterns. The upper extreme of thermal perturbation interval (+ 3°C) gives rise to an increase in adult population abundance at Nairobi (+111%) and Nyabondo (+61%), and a decrease at Kibwezi (-2%) and Malindi (-36%). At the lower extreme perturbation (-3°C) is observed a reduction in both immature and adult mosquito population in three sites (Nairobi -74%, Nyabondo -66%, Kibwezi -39%), and an increase in Malindi (+11%). A coherent non-linear pattern of population variation emerges. The maximum rate of variation is +30% population abundance for +1°C of temperature change, but also almost null and negative values are obtained. Mosquitoes are less sensitive to rainfall and both adults and immature populations display a positive quasi-linear response pattern to rainfall variation.</p> <p>Conclusions</p> <p>The non-linear temperature-dependent response is in agreement with the non-linear patterns of temperature-response of the basic bio-demographic processes. This non-linearity makes the hypothesized biological amplification of temperature effects valid only for a limited range of temperatures. As a consequence, no simple extrapolations can be done linking temperature rise with increase in mosquito distribution and abundance, and projections of <it>An. gambiae </it>s.s. populations should be produced only in the light of the local meteo-climatic features as well as other physical and biological characteristics of the landscape.</p

Insecticide-treated net (ITN) ownership, usage, and malaria transmission in the highlands of western Kenya

<p>Abstract</p> <p>Background</p> <p>Insecticide-treated bed nets (ITNs) are known to be highly effective in reducing malaria morbidity and mortality. However, usage varies among households, and such variations in actual usage may seriously limit the potential impact of nets and cause spatial heterogeneity on malaria transmission. This study examined ITN ownership and underlying factors for among-household variation in use, and malaria transmission in two highland regions of western Kenya.</p> <p>Methods</p> <p>Cross-sectional surveys were conducted on ITN ownership (possession), compliance (actual usage among those who own ITNs), and malaria infections in occupants of randomly sampled houses in the dry and the rainy seasons of 2009.</p> <p>Results</p> <p>Despite ITN ownership reaching more than 71%, compliance was low at 56.3%. The compliance rate was significantly higher during the rainy season compared with the dry season (62% vs. 49.6%). Both malaria parasite prevalence (11.8% vs. 5.1%) and vector densities (1.0 vs.0.4 female/house/night) were significantly higher during the rainy season than during the dry season. Other important factors affecting the use of ITNs include: a household education level of at least primary school level, significantly high numbers of nuisance mosquitoes, and low indoor temperatures. Malaria prevalence in the rainy season was about 30% lower in ITN users than in non-ITN users, but this percentage was not significantly different during the dry season.</p> <p>Conclusion</p> <p>In malaria hypo-mesoendemic highland regions of western Kenya, the gap between ITNownership and usage is generally high with greater usage recorded during the high transmission season. Because of the low compliance among those who own ITNs, there is a need to sensitize households on sustained use of ITNs in order to optimize their role as a malaria control tool.</p

Evaluation of two methods of estimating larval habitat productivity in western Kenya highlands

<p>Abstract</p> <p>Background</p> <p>Malaria vector intervention and control programs require reliable and accurate information about vector abundance and their seasonal distribution. The availability of reliable information on the spatial and temporal productivity of larval vector habitats can improve targeting of larval control interventions and our understanding of local malaria transmission and epidemics. The main objective of this study was to evaluate two methods of estimating larval habitat productivity in the western Kenyan highlands, the aerial sampler and the emergence trap.</p> <p>Methods</p> <p>The study was conducted during the dry and rainy seasons in 2008, 2009 and 2010. Aerial samplers and emergence traps were set up for sixty days in each season in three habitat types: drainage ditches, natural swamps, and abandoned goldmines. Aerial samplers and emergence traps were set up in eleven places in each habitat type. The success of each in estimating habitat productivity was assessed according to method, habitat type, and season. The effect of other factors including algae cover, grass cover, habitat depth and width, and habitat water volume on species productivity was analysed using stepwise logistic regression</p> <p>Results</p> <p>Habitat productivity estimates obtained by the two sampling methods differed significantly for all species except for <it>An</it>. <it>implexus</it>. For for <it>An</it>. <it>gambiae </it>s.l. and <it>An</it>. <it>funestus</it>, aerial samplers performed better, 21.5 and 14.6 folds, than emergence trap respectively, while the emergence trap was shown to be more efficient for culicine species. Seasonality had a significant influence on the productivity of all species monitored. Dry season was most productive season. Overall, drainage ditches had significantly higher productivity in all seasons compared to other habitat types. Algae cover, debris, chlorophyll-a, and habitat depth and size had significant influence with respect to species.</p> <p>Conclusion</p> <p>These findings suggest that the aerial sampler is the better of the two methods for estimating the productivity of <it>An</it>. <it>gambiae </it>s.l. and <it>An</it>. <it>funestus </it>in the western Kenya highlands and possibly other malaria endemic parts of Africa. This method has proven to be a useful tool for monitoring malaria vector populations and for control program design, and provides useful means for determining the most suitable sites for targeted interventions.</p