5 research outputs found
The structure of versutoxin (δ-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel
No full textThe structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel
No full textBackground: Versutoxin (delta-ACTX-Hv1) is the major component of the venom of the Australian Blue Mountains funnel web spider, Hadronyche versuta. delta-ACTX-Hv1 produces potentially fatal neurotoxic symptoms in primates by slowing the inactivation of voltage-gated sodium channels; delta-ACTX-Hv1 is therefore a useful tool for studying sodium channel function. We have determined the three-dimensional structure of delta ACTX-Hv1 as the first step towards understanding the molecular basis of its interaction with these channels. Results: The solution structure of delta-ACTX-Hv1, determined using NMR spectroscopy, comprises a core beta region containing a triple-stranded antiparallel beta sheet, a thumb-like extension protruding from the beta region and a C-terminal 3(10) helix that is appended to the beta domain by virtue of a disulphide bond. The beta region contains a cystine knot motif similar to that seen in other neurotoxic polypeptides. The structure shows homology with mu-agatoxin-l, a spider toxin that also modifies the inactivation kinetics of vertebrate voltage-gated sodium channels. More surprisingly, delta-ACTX-Hv1 shows both sequence and structural homology with gurmarin, a plant polypeptide. This similarity leads us to suggest that the sweet-taste suppression elicited by gurmarin may result from an interaction with one of the downstream ion channels involved in sweet-taste transduction. Conclusions: delta-ACTX-Hv1 shows no structural homology with either sea anemone or alpha-scorpion toxins, both of which also modify the inactivation kinetics of voltage-gated sodium channels by interacting with channel recognition site 3. However, we have shown that delta-ACTX-Hv1 contains charged residues that are topologically related to those implicated in the binding of sea anemone and alpha-scorpion toxins to mammalian voltage-gated sodium channels, suggesting similarities in their mode of interaction with these channels
Physical controls on salmon spawning habitat quality and embryo fitness: an integrated analysis
No full textThe research focusses on the river Lugg – a cross-border catchment and major tributary of the river Wye, the most important Atlantic salmon river in England and Wales. The problem of declining Atlantic salmon populations in the catchment is addressed through investigating recruitment from egg fertilization to the emergent life stage and beyond using multiple field-based and laboratory techniques. The approach adopted is multidisciplinary and addresses the need for holistic approaches to habitat degradation which is increasingly recognised as systemic in nature; often with multiple stressors acting interactively. The initial premise of deleterious fine sediment infiltration into spawning gravels was addressed by a sediment fingerprinting study to ascertain the provenance of infiltrated redd sediment from a range of land-use types. In addition, nine artificial redd sites were constructed and assessed for fine sediment infiltration, intragravel dissolved oxygen levels, intragravel flow velocity and other hyporheic pore water characteristics, in relation to survival to emergence over two field seasons.A study examining the quality of emergent fry was also carried out using fitness tests and individual stress levels. Additionally, a study on long-residence groundwater infiltration into the incubation environment was carried out. The main fine sediment contributor was derived from agricultural sources, particularly during wetter periods. The average contribution of fine sediment from agricultural sources was 60%. Survival ranged from 12% to 70% during the 2008 flood season and from 76% - 93% during the 2009 dry season. Fine sediment mass as a stand-alone index was only weakly correlated with survival but is thought to influence other factors; medium strength correlations of survival with dissolved oxygen, intragravel flow velocity and oxygen supply in particular were observed. Evidence of groundwater-surface water interactions were detected at two of three sites investigated and is proposed as an additional controlling mechanism for embryonic survival in the catchment. Sublethal fitness tests demonstrated variations between cohorts in the 2009 period despite a relatively small range of oxygen concentrations. The results highlight both temporal and spatial variations in spawning habitat quality, which influence not only survival to hatch but also posthatch fitness
Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation
Get PDFStudy found that treatment with recombinant human growth hormone gave significantly greater benefits in stature for children with growth hormone deficiency (GHD), Turner syndrome, Prader–Willi syndrome, chronic renal insufficency, short stature homeobox-containing gene deficiency, and those who were small for gestational age, than for untreated children. However, treatment was considered to be cost-effective at a willingness to pay threshold of £20,000–30,000 per quality-adjusted life-year gained only for children with GHD, although the analysis is subject to a range of important uncertaintie
Methods of prediction and prevention of pre-eclampsia: Systematic reviews of accuracy and effectiveness literature with economic modelling
Get PDF© Queen's Printer and Controller of HMSO 2008. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided
that suitable acknowledgement is made and the reproduction is not associated with any form of advertising.Objectives: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia. Data sources: Major electronic databases were searched to January 2005 at least. Review methods: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model. Results: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index > 34, α-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both preeclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of preeclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from £5 for blood tests such as serum uric acid to approximately £20 for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately £9000. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case. Conclusions: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.National Institute for Health Researc
