851 research outputs found
Heterogeneity of passenger exposure to air pollutants in public transport microenvironments
Epidemiologic studies have linked human exposure to pollutants with adverse health effects. Passenger exposure in public transport systems contributes an important fraction of daily burden of air pollutants. While there is extensive literature reporting the concentrations of pollutants in public transport systems in different cities, there are few studies systematically addressing the heterogeneity of passenger exposure in different transit microenvironments, in cabins of different transit vehicles and in areas with different characteristics. The present study investigated PM2.5 (particulate matter with aerodynamic diameters smaller than 2.5Όm), black carbon (BC), ultrafine particles (UFP) and carbon monoxide (CO) pollutant concentrations in various public road transport systems in highly urbanized city of Hong Kong. Using a trolley case housing numerous portable air monitors, we conducted a total of 119 trips during the campaign. Transit microenvironments, classified as 1). busy and secondary roadside bus stops; 2). open and enclosed termini; 3). above- and under-ground Motor Rail Transport (MTR) platforms, were investigated and compared to identify the factors that may affect passenger exposures. The pollutants inside bus and MTR cabins were also investigated together with a comparison of time integrated exposure between the transit modes. Busy roadside and enclosed termini demonstrated the highest average particle concentrations while the lowest was found on the MTR platforms. Traffic-related pollutants BC, UFP and CO showed larger variations than PM2.5 across different microenvironments and areas confirming their heterogeneity in urban environments. In-cabin pollutant concentrations showed distinct patterns with BC and UFP high in diesel bus cabins and CO high in LPG bus cabins, suggesting possible self-pollution issues and/or penetration of on-road pollutants inside cabins during bus transit. The total passenger exposure along selected routes, showed bus trips had the potential for higher integrated passenger exposure compared to MTR trips. The present study may provide useful information to better characterize the distribution of passenger exposure pattern in health assessment studies and the results also highlight the need to formulate exposure reduction based air policies in large cities. © 2015 Elsevier Ltd.postprin
Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue
Artemisinin, isolated from the traditional Chinese medicinal plant qÄ«ng hÄo éèż
(Artemisia annua) and its derivatives are used for treatment of malaria. With
treatment failures now being recorded for the derivatives and companion drugs
used in artemisinin combination therapies new drug combinations are urgently
required. The amino-artemisinins artemiside and artemisone display optimal
efficacies in vitro against asexual and sexual blood stages of the malaria parasite
Plasmodium falciparum and are active against tumour cell lines. In continuing
the evolution of combinations of the amino-artemisinins with new drugs, we
examine the triterpenoid quinone methide celastrol isolated from the traditional
Chinese medicinal plant lĂ©i gĆng tĂ©ng é·ć
Źè€ (Tripterygium wilfordii). This
compound is redox active, and has attracted considerable attention because
of potent biological activities against manifold targets. We report that celastrol
displays good IC50 activities ranging from 0.50â0.82 ”M against drug-sensitive
and resistant asexual blood stage Pf, and 1.16 and 0.28 ”M respectively against
immature and late stage Pf NF54 gametocytes. The combinations of celastrol
with each of artemisone and methylene blue against asexual blood stage Pf are
additive. Given that celastrol displays promising antitumour properties, we
examined its activities alone and in combinations with amino-artemisinins
against human liver HepG2 and other cell lines. IC50 values of the aminoartemisinins and celastrol against HepG2 cancer cells ranged from
0.55â0.94 ”M. Whereas the amino-artemisinins displayed notable
selectivities (SI > 171) with respect to normal human hepatocytes, in
contrast, celastrol displayed no selectivity (SI < 1). The combinations of
celastrol with artemiside or artemisone against HepG2 cells are synergistic.
Given the promise of celastrol, judiciously designed formulations or structural
modifications are recommended for mitigating its toxicity.https://www.frontiersin.org/journals/pharmacologyBiochemistr
The artemiside-artemisox-artemisone-m1 tetrad : efficacies against blood stage p. falciparum parasites, dmpk properties, and the case for artemiside
Because of the need to replace the current clinical artemisinins in artemisinin combination
therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the
thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin
(DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile
metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite
M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent
with artemiside and artemisone in vitro against asexual P. falciparum (Pf ) blood stage parasites (IC50
1.5â2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM
early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like
other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism
and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside,
artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax
value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold
higher than that attained following administration of artemisone alone. Given that efficacy of short
half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is
apparent that artemiside will be more active than artemisone in vivo, due to additive effects of
the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater
efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following
administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred
drug for incorporation into rational new artemisinin combination therapies.Supplementary Material 1: S1 Efficacy of artemisox, dose response curves against asexual, and gametocyte blood stage parasites: Figure S1aâe; S2 Efficacy of M1, dose response curves against asexual, and gametocyte blood stage parasites: Figure S2aâd; S3 Pharmacokinetics and metabolism, circulating concentrations of artemiside, artemisox, and artemisone: Table S3aâf, LC-MS/MS chromatograms of M1 Figure S3aâc; S4 In vitro efficacy dataâ previously published data for artemiside, artemisone, M1: Table S4aâc; S5 In vivo efficacy dataâ previously published data for artemiside, artemisone: Table S5; S6 Neurotoxicity dataâpreviously published neurotoxicity data for DHA, artesunate, artemiside, artemisone: Table S6.Supplementary Material 2: PDF copy of reference [37].The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package, a South African National Research Foundation (SA NRF) grant, and by a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant and the Department of Science and Innovation and SA NRF South African Research Chairs Initiative (SARChI) Grant.https://www.mdpi.com/journal/pharmaceuticsam2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC
The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside
Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5â2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies
Activities of 11âazaartemisinin and Nâsulfonyl derivatives against asexual and transmissible malaria parasites
Dihydroartemisinin (DHA), either used in its own right or as the active drug generated inâ
vivo from the other artemisinins in current clinical useâartemether and artesunateâinduces quiescence in ringâstage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11âazaartemisinin 5 and selected Nâsulfonyl derivatives were screened against intraerythrocytic asexual stages of drugâsensitive Pf NF54 and drugâresistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values 2000 toward asexual parasites. Overall, the readily accessible 11âazaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisininâresistant parasites.http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-71872018-12-19hj2018Biochemistr
Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma
Background and purposeWhether liver resection or ablation should be the first-line treatment for very early/early hepatocellular carcinoma (HCC) in patients who are candidates for both remains controversial. The aim of this study was to determine if the newly-developed Albumin-Bilirubin (ALBI) grade might help in treatment selections and to evaluate the survival of patients treated with liver resection and radiofrequency ablation (RFA).MethodsPatients with BCLC stage 0/A HCC who were treated with curative liver resection and RFA from 2003 to 2013 were included. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Liver function and its impact on survival was assessed by the ALBI score. Overall and disease-free survivals were compared between the two groups.Results488 patients underwent liver resection (n = 318) and RFA (n = 170) for BCLC stage 0/A HCC during the study period. Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC in the whole cohort. After propensity score matching, liver resection offered superior overall survival and disease-free survival to RFA in patients with ALBI grade 1 (P = 0.0002 and P ConclusionsLiver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC. The ALBI grade could identify those patients with worse liver function who did not gain any survival advantage from curative liver resection
Optimal 10-aminoartemisinins with potent transmission-blocking capabilities for new artemisinin combination therapiesâactivities against blood stage P. falciparum including PfKI3 C580Y mutants and liver stage P. berghei parasites
We have demonstrated previously that amino-artemisinins including artemiside and
artemisone in which an amino group replaces the oxygen-bearing substituents attached
to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether
and artesunate, display potent activities in vitro against the asexual blood stages
of Plasmodium falciparum (Pf ). In particular, the compounds are active against late
blood stage Pf gametocytes, and are strongly synergistic in combination with the
redox active drug methylene blue. In order to fortify the eventual selection of optimum
amino-artemisinins for development into new triple combination therapies also active
against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins
based on the easily accessible and inexpensive DHA-piperazine. The latter was
converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were
screened together with the comparator drugs DHA and the hitherto most active
amino-artemisinins artemiside and artemisone against asexual and sexual blood stages
of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins
bearing aryl-urea and -amide groups are potently active against both asexual, and
late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to
those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more
active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early
results indicate these compounds tend not to display reduced susceptibility against
parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside
and artemisone will enable the development of new combination therapies that by virtue
of the amino-artemisinin component itself will possess intrinsic transmission-blocking
capabilities and may be effective against artemisinin resistant falciparum malaria.Supplementary Table 1 | In vitro activities of selected amino-artemisinins against
liver stage P. berghei, dose response curves and cytotoxicities.Supplementary Material comprises experimental details for
synthesis and characterization data of the amino-artemisinins,
and dose response curves for the in vitro P. berghei sporozoite
stage efficacy assays recorded in Excel format in CDD Vault:
UCSD CDD_Vault_Export_RESULTS_KDE_03-25-2019.This work was funded by the South African Medical Research
Council (MRC) Flagship Project MALTB-Redox with funds
from National Treasury under its Economic Competitiveness
and Support Package to RH (MRC-RFA-UFSP-01-2013), the
South African MRC Strategic Health Innovation Partnership
(SHIP) grant, a South African MRC Collaborative Center
for Malaria Research grant and South African National
Research Foundation grants (UID 84627) to L-MB and to
RH (UIDs 90682 and 98934). EW was supported by grants
from the NIH (R01 AI090141-02), and Medicines for Malaria
Venture, Geneva.http://www.frontiersin.org/Chemistryam2020BiochemistryGeneticsMicrobiology and Plant Patholog
Artemisone and artemiside - potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages
The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives towards the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes in the low nM range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displays notable synergism. These data suggest that modulation of redox-homeostasis likely is an important druggable process, particularly in gametocytes, and thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package to Richard K. Haynes; a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant, and a South African National Research Foundation grant (UID 84627) to Lyn-Marie Birkholtz; and South African National Research Foundation grants to Richard K. Haynes (UIDs 90682 and 98934). Donatella Taramelli and Sarah D'Alessandro acknowledge the support from the Global Health Program of the Bill & Melinda Gates Foundation (grant OPP1040394 to Donatella Taramelli, Pietro Alano coordinator, and COST Action CM1307).http://aac.asm.org2019-02-01hj2018Biochemistr
Towards a global partnership model in interprofessional education for cross-sector problem-solving
Objectives
A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available.
Methods
This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in studentsâ data.
Results
We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretestâposttest differences in studentsâ readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in studentsâ social interaction anxiety after the IPE simulation.
Conclusions
The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education
Observation of electron-antineutrino disappearance at Daya Bay
The Daya Bay Reactor Neutrino Experiment has measured a non-zero value for
the neutrino mixing angle with a significance of 5.2 standard
deviations. Antineutrinos from six 2.9 GW reactors were detected in
six antineutrino detectors deployed in two near (flux-weighted baseline 470 m
and 576 m) and one far (1648 m) underground experimental halls. With a 43,000
ton-GW_{\rm th}-day livetime exposure in 55 days, 10416 (80376) electron
antineutrino candidates were detected at the far hall (near halls). The ratio
of the observed to expected number of antineutrinos at the far hall is
. A rate-only analysis
finds in a
three-neutrino framework.Comment: 5 figures. Version to appear in Phys. Rev. Let
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