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From bones to blood pressure, developing novel biologic approaches targeting the osteoprotegein pathway for pulmonary vascular disease
No full textAbstractOsteoprotegerin (tnfsf11b, OPG) is a soluble member of the TNF superfamily originally described as an important regulator of osteoclastogenesis almost 20years ago. OPG is a heparin-binding secreted glycoprotein that exists as a 55–62kDa monomer or a 110–120kDa disulphide-linked homodimer. Acting as a soluble decoy receptor for RANKL, OPG actively regulates RANK signalling, and thereby osteoclastogenesis. OPG has subsequently been shown to also be a decoy receptor TNF related apoptosis inducing-ligand (tnfsf10, TRAIL, Apo2L). TRAIL is a type II transmembrane protein that is widely expressed in a variety of human tissues, including the spleen, lung, and prostate. Through binding to TRAIL, OPG can inhibit TRAIL-induced apoptosis of cancer cells. More recently, OPG has been demonstrated to be secreted by, and influence, vascular smooth muscle cells phenotype particularly related to vascular calcification and pulmonary vascular remodelling. In pulmonary artery smooth muscle cell (PASMC) suppression of BMP, induction of 5-HT and IL-1 signalling have been shown to stimulate the release of OPG in vitro, which causes cell migration and proliferation. Patients with idiopathic PAH (IPAH) demonstrate increased circulating and tissue levels of OPG, and circulating serum levels predict survival. In pre-clinical models, OPG levels correlate with disease severity. Since OPG is a naturally circulating protein, we are investigating the potential of novel biologic antibody therapies to rescue PAH phenotype in disease models. Further pre-clinical and mechanistic data are forthcoming, but we believe current published data identify OPG as an exciting and novel therapeutic target in PAH
Characterizing spheres by an immersion in Euclidean spaces
No full textAbstractIn this paper we study compact immersed orientable hypersurfaces in the Euclidean space Rn+1 and show that suitable restrictions on the tangential and normal components of the immersion give different characterizations of the spheres
An intradural lumbar disc fragment with free migration: A case of a missed intradural disc herniation
No full textAbstractIntroductionIntradural lumbar disc herniation (ILDH) is a very rare pathological entity. The pathomechanisms and the natural course remain unclear.Case presentationThe authors present the case of a 58-year-old Germans male with repetitive microdiscectomies (MD) and intraoperative missed diagnosis of ILDH. The patient underwent standard MD due to lumbar disc herniation (LDH) at the level L4/5. Incidental durotomy (ID) was sealed with a ventromedial patch. Postoperative course was uneventful. 14months later the patient presented with a L4 radiculopathy, having his second MD at the level L3/4. At this point the radiological images showed already a free floating intradural fragment at the level S1, clinically not significant. As in the previous surgery, the postoperative course was uneventful. After 18months, he presented again complaining of low back pain and electric-like attacks of pain along the right L5 root for the prior five months. Contrast-MRI revealed that the known intradural disc-mass migrated from S1 to the level L4/5. A left L4 hemilaminectomy was performed. The durotomy identified a hard, white, shiny mass. The patient was pain-free until the last follow-up at 13months.ConclusionsIntraoperative manipulation of disc fragments in the presence of an ID potentially leads to iatrogenic ILDH
A framework for a joint hydro-meteorological-social analysis of drought
No full textAbstractThis article presents an innovative framework for analysing environmental governance challenges by focusing on their Drivers, Responses and Impacts (DRI). It builds on and modifies the widely applied Drivers, Pressures, States, Impacts and Responses (DPSIR) model. It suggests, firstly and most importantly, that the various temporal and spatial scales at which Drivers, Responses and Impacts operate should be included in the DRI conceptual framework. Secondly, the framework focuses on Drivers, Impacts and Responses in order to provide a parsimonious account of a drought system that can be informed by a range of social science, humanities and science data. ‘Pressures’ are therefore considered as a sub-category of ‘Drivers’. ‘States’ are a sub-category of ‘Impacts’. Thirdly, and most fundamentally in order to facilitate cross-disciplinary research of droughts, the DRI framework defines each of its elements, ‘Drivers’, ‘Pressures’, ‘States’, ‘Impacts’ and ‘Responses’ as capable of being shaped by both linked natural and social factors. This is different from existing DPSIR models which often see ‘Responses’ and ‘Impacts’ as located mainly in the social world, while ‘States’ are considered to be states within the natural environment only. The article illustrates this argument through an application of the DRI framework to the 1976 and 2003–6 droughts. The article also starts to address how - in cross-disciplinary research that encompasses physical and social sciences – claims about relationships between Drivers as well as Impacts of and Responses to drought over time can be methodologically justified. While the DRI framework has been inductively developed out of research on droughts we argue that it can be applied to a range of environmental governance challenges
Effectiveness of insecticide-treated bednets in malaria prevention in Haiti: a case-control study
No full textSummaryBackgroundInsecticide-treated bednets (ITNs) are effective in preventing malaria where vectors primarily bite indoors and late at night, but their effectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the effectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake.MethodsIn this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defined by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioefficacy and entomological data were collected.FindingsWe enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not significantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68–1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45–1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioefficacy, and no permethrin resistance among local mosquitoes.InterpretationWe found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised.FundingThe Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the US-based Centers for Disease Control and Prevention (CDC)
Adsorption behavior of lead onto a new class of functionalized silica gel
No full textAbstractIn this study the surface of silica gel was functionalized with 2-thiophenecarbonyl, 2-furoyl and l-proline. The synthesized materials were characterized by fourier transform infrared (FTIR) spectroscopy and scanning electron microscope (SEM) with energy dispersive X-ray analyzer (EDX). Batch adsorption studies were carried out to analyze the adsorption of the lead ion from aqueous solution. The factors influencing % adsorption of Pb(II) onto the silica gel and functionalized silica gel such as initial pH value of the Pb(II) ion solution, adsorbent dose, initial Pb(II) ion concentration, contact time and temperature were investigated. Langmuir and Freundlich isotherm models were used to determine the isotherm parameters associated with the adsorption process. Kinetic data were analyzed considering pseudo-first order, pseudo-second order and intraparticle diffusion approaches. The latter two mechanisms seem to be significant in the rate-controlling step. Negative values of Gibb's free energy change (ΔG°) showed that the adsorption was feasible and spontaneous and negative values of enthalpy change (ΔH°) confirmed exothermic adsorption
One-pot sequential synthesis of O-(halo-substituted benzyl) hydroxylammonium salts
No full textAbstractIn this study, we described a simple one-pot preparation of O-(halo-substituted benzyl) hydroxylamine derivatives by O-benzylation of N-hydroxyurethane, followed by basic N-deprotection. The advantages of the method were the chemo- and regio-selectivity in obtaining the desired O-benzyl hydroxylammonium salts in a high yield as well as the simplicity of the purification process
Navigating the authority paradox: Practising objectivity in environmental expertise
No full textAbstractWe empirically reveal how environmental experts interpret the objectivity norm while navigating the authority paradox. The paradox here is that while there is a need for objective scientific advice, such advice is only to be acquired from experts and expert agencies whose objectivity and, hence, authority are contested. Viewed through the lens of practice, we identify what practitioners at the PBL Netherlands Environmental Assessment Agency understand by objectivity. Using this paradigmatic case, we show how practitioners renegotiate the meaning of objectivity while seeking to engage with new policy actors and extended peers in an independent, rigorous and legitimate manner. Successfully navigating the authority paradox is related to skilfully representing and adapting to various meanings of objectivity. Experts and experts agencies accordingly need reflexive skills to recognise which meanings of objectivity they ascribe to and which ones are invoked in public debates. Environmental experts who are able to loosely connect diverse objectivity conceptions are more likely considered as trustworthy and authoritative partners in environmental science-policy interfaces
Theoretical studies on benzimidazole and imidazo[1,2-a]pyridine derivatives as Polo-like kinase 1 (Plk1) inhibitors: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking approach
No full textAbstractMolecular modeling studies were carried out on a series of benzimidazole and imidazo[1,2-a]pyridines as Plk1 inhibitors. Based on the pharmacophore model, we obtained a five-featured hypothesis AADRR, with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic rings. An atom-based 3D-QSAR model was predicted for 36 training set (R2=0.9475, SD=0.1927, F=99.3) and nine test set (Q2=0.6519, RMSE=0.4044, Pearson R=0.834) compounds using a pharmacophore-based alignment. From these results, AADRR pharmacophore feature was chosen as the best common pharmacophore hypothesis, whereas the atom-based 3D-QSAR results explain the importance of hydrophobic and electron-withdrawing features for the most active compound 32. The dataset molecules were docked into the active site of Plk1, which shows acceptable hydrogen bond interactions with residues Cys133, Asp194, Glu131, Lys82 and Glu140 and also shows further hydrogen bond interactions with hydrophobic residues Cys67, Leu59 and Arg136. These results can be helpful for further design of novel Plk1 inhibitors