An Efficient, Green Chemical Synthesis of the Malaria\ud Drug, Piperaquine

To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings. We used in-process analytical technologies (IPAT; HPLC) and a program of experiments to develop a synthesis of piperaquine that avoids the presence of a toxic impurity in the API and is optimized for overall yield and operational simplicity. A green-chemical synthesis of piperaquine is described that proceeds in 92 – 93 % overall yield. The chemistry is robust and provides very pure piperaquine tetraphosphate salt (> 99.5 %). The overall process utilizes modest amounts (about 8 kg/kg) of 2-propanol and ethyl acetate as the only organic materials not incorporated into the API; roughly 60 % of this waste can be recycled into the production process. This process also completely avoids the formation of a toxic impurity commonly seen in piperaquine that is otherwise difficult to remove. An efficient synthesis of piperaquine is described that may be useful for application in resource-poor settings as a means of expanding access to and reducing the cost of ACTs

X-ray Emission from Nitrogen-Type Wolf-Rayet Stars

We summarize new X-ray detections of four nitrogen-type Wolf-Rayet (WR) stars obtained in a limited survey aimed at establishing the X-ray properties of WN stars across their full range of spectral subtypes. None of the detected stars is so far known to be a close binary. We report Chandra detections of WR 2 (WN2), WR 18 (WN4), and WR 134 (WN6), and an XMM-Newton detection of WR79a (WN9ha). These observations clearly demonstrate that both WNE and WNL stars are X-ray sources. We also discuss Chandra archive detections of the WN6h stars WR 20b, WR 24, and WR 136 and ROSAT non-detections of WR 16 (WN8h) and WR 78 (WN7h). The X-ray spectra of all WN detections show prominent emission lines and an admixture of cool (kT 2 keV) plasma. The hotter plasma is not predicted by radiative wind shock models and other as yet unidentified mechanisms are at work. Most stars show X-ray absorption in excess of that expected from visual extinction (Av), likely due to their strong winds or cold circumstellar gas. Existing data suggest a falloff in X-ray luminosity toward later WN7-9 subtypes, which have higher Lbol but slower, denser winds than WN2-6 stars. This provides a clue that wind properties may be a more crucial factor in determining emergent X-ray emission levels than bolometric luminosity.Comment: 42 pages, 5 tables, 10 figure

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual\u27s risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig\u27s potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.)

Inside the Horizon with AdS/CFT

Using the eternal BTZ black hole as a concrete example, we show how spacelike singularities and horizons can be described in terms of AdS/CFT amplitudes. Our approach is based on analytically continuing amplitudes defined in Euclidean signature. This procedure yields finite Lorentzian amplitudes. The naive divergences associated with the Milne type singularity of BTZ are regulated by an $i\epsilon$ prescription inherent in the analytic continuation and a cancellation between future and past singularities. The boundary description corresponds to a tensor product of two CFTs in an entangled state, as in previous work. We give two bulk descriptions corresponding to two different analytic continuations. In the first, only regions outside the horizon appear explicitly, and so amplitudes are manifestly finite. In the second, regions behind the horizon and on both sides of the singularity appear, thus yielding finite amplitudes for virtual particles propagating through the black hole singularity. This equivalence between descriptions only outside and both inside and outside the horizon is reminiscent of the ideas of black hole complementarity.Comment: 31 pages, 6 figure

Initial Conditions for Inflation

Free scalar fields in de Sitter space have a one-parameter family of states invariant under the de Sitter group, including the standard thermal vacuum. We show that, except for the thermal vacuum, these states are unphysical when gravitational interactions are included. We apply these observations to the quantum state of the inflaton, and find that, at best, dramatic fine tuning is required for states other than the thermal vacuum to lead to observable features in the CMBR anisotropy.Comment: 31 pages, 4 figure

Regions of High Out-Of-Hospital Cardiac Arrest Incidence and Low Bystander CPR Rates in Victoria, Australia

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains a major public health issue and research has shown that large regional variation in outcomes exists. Of the interventions associated with survival, the provision of bystander CPR is one of the most important modifiable factors. The aim of this study is to identify census areas with high incidence of OHCA and low rates of bystander CPR in Victoria, Australia. METHODS: We conducted an observational study using prospectively collected population-based OHCA data from the state of Victoria in Australia. Using ArcGIS (ArcMap 10.0), we linked the location of the arrest using the dispatch coordinates (longitude and latitude) to Victorian Local Government Areas (LGAs). We used Bayesian hierarchical models with random effects on each LGA to provide shrunken estimates of the rates of bystander CPR and the incidence rates. RESULTS: Over the study period there were 31,019 adult OHCA attended, of which 21,436 (69.1%) cases were of presumed cardiac etiology. Significant variation in the incidence of OHCA among LGAs was observed. There was a 3 fold difference in the incidence rate between the lowest and highest LGAs, ranging from 38.5 to 115.1 cases per 100,000 person-years. The overall rate of bystander CPR for bystander witnessed OHCAs was 62.4%, with the rate increasing from 56.4% in 2008-2010 to 68.6% in 2010-2013. There was a 25.1% absolute difference in bystander CPR rates between the highest and lowest LGAs. CONCLUSION: Significant regional variation in OHCA incidence and bystander CPR rates exists throughout Victoria. Regions with high incidence and low bystander CPR participation can be identified and would make suitable targets for interventions to improve CPR participation rates

The SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to Recruit Its Cul5-Containing Ubiquitin Ligase Complex

The HIV-1 viral infectivity factor (Vif) protein recruits an E3 ubiquitin ligase complex, comprising the cellular proteins elongin B and C (EloBC), cullin 5 (Cul5) and RING-box 2 (Rbx2), to the anti-viral proteins APOBEC3G (A3G) and APOBEC3F (A3F) and induces their polyubiquitination and proteasomal degradation. In this study, we used purified proteins and direct in vitro binding assays, isothermal titration calorimetry and NMR spectroscopy to describe the molecular mechanism for assembly of the Vif-EloBC ternary complex. We demonstrate that Vif binds to EloBC in two locations, and that both interactions induce structural changes in the SOCS box of Vif as well as EloBC. In particular, in addition to the previously established binding of Vif's BC box to EloC, we report a novel interaction between the conserved Pro-Pro-Leu-Pro motif of Vif and the C-terminal domain of EloB. Using cell-based assays, we further show that this interaction is necessary for the formation of a functional ligase complex, thus establishing a role of this motif. We conclude that HIV-1 Vif engages EloBC via an induced-folding mechanism that does not require additional co-factors, and speculate that these features distinguish Vif from other EloBC specificity factors such as cellular SOCS proteins, and may enhance the prospects of obtaining therapeutic inhibitors of Vif function

Caregiving process and caregiver burden: Conceptual models to guide research and practice

BACKGROUND: Parental care for a child with a developmental disability is an enormous responsibility, one that can far exceed that of typical parental care. While most parents adapt well to the situation of caring for a child with a disability, some do not. To understand parents' adaptations to their children's disabilities, the complex nature of stress processes must be accounted for and the constructs and factors that play a role in the caregiving must be considered. DISCUSSION: Evidence suggests that there is considerable variation in how caregivers adapt to their caregiving demands. Many studies have sought to qualify the association between caregiving and health outcomes of the caregivers. Contextual factors such as SES, child factors such as child behaviour problems and severity of disability, intra-psychic factors such as mastery and self-esteem, coping strategies and social supports have all been associated with psychological and/or physical outcome or parents or primary caregivers. In reviewing these issues, the literature appears to be limited by the use of traditional analytic approaches which examine the relationship between a factor and an outcome. It is clear, however, that changes to single factors, as represented in these studies, occur very rarely even in the experimental context. The literature has also been limited by lack of reliance on specific theoretical frameworks. SUMMARY: This conceptual paper documents the state of current knowledge and explores the current theoretical frameworks that have been used to describe the caregiving process from two diverse fields, pediatrics and geriatrics. Integration of these models into one comprehensive model suitable for this population of children with disabilities and their caregivers is proposed. This model may guide future research in this area