Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent

Assessing ecological resilience to human induced environmental change in shallow lakes

Sudden unpredictable changes in ecosystems are an increasing source of concern because of their inherent unpredictability and the difficulties involved in restoration. Our understanding of the changes that occur across different trophic levels and the form of this change is lacking. This is especially true of large shallow lakes, where characteristics such as fetch and depth are close to theoretical boundary values for hysteretic behaviour. The development of reliable indicators capable of predicting these changes has been the focus of much research in recent years. The success of these early warning indicators (EWIs) has so far been mixed. There remain many unknowns about how they perform under a wide variety of conditions and parameters. Future climate change is predicted to have a wide range of impacts through the interaction of combined pressures, making the understanding of EWIs and the in-lake processes that occur during regime shifts imperative. Loch Leven, Scotland, UK, is a large shallow lake with a history of eutrophication, research and management and as such is an ideal study site to better understand resilience and regime shifts under a range of interacting stressors. The objectives of this research are to: (1) analyse long term data to identify the occurrence of common tipping points within the chemical (water column nutrient concentrations) and biological (macrophytes, phytoplankton, zooplankton) components of the loch, then test these tipping points using five statistical early warning indicators (EWIs) across multiple rolling window sizes; and (2) quantify the changes in lake ecology using a before/after analysis and testing for non-linearity, combined with modelling using the aquatic ecosystem process model PCLake to determine the level of resilience following a regime shift during recovery from eutrophication; (3) using PCLake, examine the sensitivity of Loch Leven to regime shifts in the face of predicted environmental change (e.g. climate change, nutrient pollution). Statistical analysis identified tipping points across all trophic levels included, from physical and chemical variables through to apex predators. The success of EWIs in predicting the tipping points was highly dependent on the number of EWIs used, with window size having a smaller impact. The 45% window size had the highest overall accuracy across all EWIs but only detected 16.5% more tipping points than the window size with the lowest overall accuracy. Differences between individual EWI performance and usage of them as a group was substantial with a 29.7% increase between the two. In both individual and group use of EWIs, false positives (early warning without a tipping point) were more common than true positives (tipping point preceded by EWI), creating significant doubts about their reliability as management tools. Significant change was seen across multiple variables and trophic levels in the before/after analysis following sudden recovery from eutrophication, with most variables also showing evidence of non-linear change. Modelling of responses to nutrient loading for chlorophyll, zooplankton and macrophytes, under states from before and after the shift, indicate hysteresis and thus the presence of feedback mechanisms. The modelling of responses to nutrient loading and predicted climate change in temperature and precipitation demonstrated that increases in temperature and decreases in summer precipitation individually had large impacts on chlorophyll and zooplankton at medium to high phosphorus (P) loads. However, modelling of the combined effects of these changes resulted in the highest lake chlorophyll concentrations of all tested scenarios. At low P loads higher temperatures and increased winter precipitation had the greatest impact on system resilience with a lower Critical Nutrient Load (CNL). The difference between chlorophyll and zooplankton as opposed to macrophytes was in the presence of a lower CNL for the increased winter precipitation-only scenarios which was not seen in the macrophytes. This highlights the potential role of high winter inputs potentially loaded with particulate matter in reducing resilience at lower P loads. This research has highlighted the vulnerability and low resilience of Loch Leven to environmental change. The presence of multiple tipping points and high levels of EWI activity show a high level of flexibility in the system. Coupled with the occurrence of widespread trophic change during a sudden recovery and a small level of hysteresis and high levels of sensitivity to climate change, the low levels of resilience become clear. The impact of lake-specific characteristics such as moderate depth, large fetch and a heterogeneous bed morphology is particularly evident in the limitations on macrophyte cover and the reliance on zooplankton to determine the hysteresis offset (amount of phosphorus (P) loading between the two CNL). The presence of these characteristics can be used to identify other lakes vulnerable to change. Improving the predictive capabilities of resilience indicators such as EWIs, and better understanding of the ecological changes that occur during non-linear change in response to recovery and climate change, can help target relevant ecosystem components for preventative management. These actions may become necessary under even the most conservative estimates of environmental change

Mouthwashes for the control of supragingival biofilm and gingivitis in orthodontic patients: evidence-based recommendations for clinicians

Properly performed daily mechanical biofilm control is the most important prevention strategy for periodontal diseases. However, proper mechanical biofilm control is not performed effectively by the majority of the population, mainly due to lack of motivation and of manual dexterity. Local biofilm retention factors may aggravate home oral hygiene quality. For this reason, patients wearing fixed orthodontic appliances comprise a group that may benefit from the daily use of mouthwashes. The purpose of this review was to perform a systematic search in the literature on antiseptics used to control supragingival biofilm and gingivitis in orthodontic patients. Six studies investigating the effect of chlorhexidine and 5 studies evaluating the effect of the daily use of antiseptics were found. Chlorhexidine showed better results in reducing plaque and gingivitis. However, because of its adverse effects after continuous use, it should not be indicated for long-term periods. Among the agents considered for daily use, the fixed combination of essential oils was the only one evaluated in a clinical trial, in which a comparative group presented a statistically significant clinical impact. There is no direct evidence supporting the indication of antiseptic agents for orthodontic patients other than chlorhexidine and essential oils. It can be concluded that, for patients undergoing orthodontic treatment, chlorhexidine should be considered for treating acute gingival inflammation, whereas essential oils should be indicated for long-term daily use in controlling supragingival biofilm

Shear bond strength of metallic and ceramic brackets using color change adhesives

OBJECTIVE: To determine the shear bond strength of orthodontic brackets using color change adhesives that are supposed to aid in removing excess of bonding material and compare them to a traditional adhesive. METHODS: Ninety metallic and ninety ceramic brackets were bonded to bovine incisors using two color change adhesives and a regular one. A tensile stress was applied by a universal testing machine. The teeth were observed in a microscope after debonding in order to determine the Adhesive Remnant Index (ARI). RESULTS: The statistical analysis (ANOVA, Tukey, and Kruskall-Wallis tests) demonstrated that the mean bond strength presented no difference when metallic and ceramic brackets were compared but the bond resistance values were significantly different for the three adhesives used. The most common ARI outcome was the entire adhesive remaining on the enamel. CONCLUSIONS: The bond strength was similar for metallic and ceramic brackets when the same adhesive system was used. ARI scores demonstrated that bonding with these adhesives is safe even when ceramic brackets were used. On the other hand, bond strength was too low for orthodontic purposes when Ortho Lite Cure was used

Efeito da amarração em Ortodontia, com ligaduras elastoméricas e de aço inoxidável, na saúde periodontal

OBJETIVO: o presente estudo avaliou clinicamente as condições periodontais de um grupo teste e um grupo controle utilizando-se os seguintes três sistemas de indexação periodontal: índice de biofilme, índice de sangramento e profundidade de sondagem. MÉTODOS: o grupo teste foi composto por 20 indivíduos com média etária de 13,5 anos, submetido ao tratamento ortodôntico fixo, que recebeu duas formas de ligaduras: a elastomérica e a de aço inoxidável. Os resultados foram comparados entre si e com um grupo controle, sem tratamento ortodôntico, composto de 15 indivíduos com média etária de 15,3 anos. As mensurações foram realizadas previamente ao tratamento ortodôntico (T1) e seis meses após a colocação do aparelho ortodôntico fixo (T2); e, no grupo controle, após seis meses da mensuração inicial (T2). Ambos os grupos foram orientados quanto à higiene bucal, segundo a técnica de Bass, antes do início do tratamento. RESULTADOS E CONCLUSÕES: os resultados das análises das faces dentárias demonstraram um aumento estatisticamente significativo nos índices de biofilme (P=0,000), sangramento gengival (P=0,000) e profundidade de sondagem (P=0,000), quando T1 e T2 e os grupos foram comparados; entretanto, não foram encontradas diferenças estatisticamente significativas entre as ligaduras elastoméricas e de aço inoxidável na avaliação desses índices periodontais