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Sample records for chloroquine reduces arylsulphatase

  1. Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis.

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    Rodolfo Thomé

    Full Text Available BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg cells and suppressive Dendritic Cells (DCs, to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ, an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE, an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55 peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of

  2. The synergistic effect of everolimus and chloroquine on endothelial cell number reduction is paralleled by increased apoptosis and reduced autophagy occurrence.

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    Anna Grimaldi

    Full Text Available Endothelial Progenitor Cells (EPCs, a minor subpopulation of the mononuclear cell fraction in peripheral blood, play a critical role in cancer development as they contribute to angiogenesis-mediated pathological neovascularization. In response to tumor cytokines, including VEGF, EPCs mobilize from the bone marrow into the peripheral circulation and move to the tumor bed where they incorporate into sprouting neovessels. In the present study, we evaluated the effects of everolimus (Afinitor, Novartis, a rapamycin analogue, alone or in combination with chloroquine, a 4-alkylamino substituted quinoline family member, one of the autophagy inhibitors, on EPCs biological functions. We found that either everolimus or chloroquine induce growth inhibition on EPCs in a dose-dependent manner after 72 h from the beginning of incubation. The combined administration of the two drugs to EPC was synergistic in inducing growth inhibition; in details, the maximal pharmacological synergism between everolimus and chloroquine in inducing growth inhibition on EPCs cells was recorded when chloroquine was administered 24 h before everolimus. Moreover, we have studied the mechanisms of cell death induced by the two agents alone or in combination on EPCs and we have found that the synergistic effect of combination on EPC growth inhibition was paralleled by increased apoptosis induction and reduced autophagy. These effects occurred together with biochemical features that are typical of reduced autophagic death such as increased co-immunoprecipitation between Beclin 1 and Bcl-2. Chloroquine antagonized the inhibition of the activity of Akt→4EBP1 axis mediated by everolimus and at the same time it blocked the feed-back activation of Erk-1/2 induced by RAD in EPCs. These data suggest a new strategy in order to block angiogenesis in tumours in which this process plays a key role in both the sustainment and spreading of cancer cells.

  3. Arylsulphatase activity and sulphate content in relation to crop rotation and fertilization of soil

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    Siwik-Ziomek, Anetta; Lemanowicz, Joanna; Koper, Jan

    2016-07-01

    The aim of the study was to investigate the effect of varying rates of FYM (0, 20, 40, 60 Mg ha-1) and nitrogen N0, N1, N2, and N3 on the content of sulphate sulphur (VI) and the activity of arylsulphatase, which participates in the transformations of this element in Haplic Luvisol. The study report is based on a long-term field experiment with two different crop rotations: A - recognized as exhausting the humus from soil and B - recognized as enriching the soil with humus. During the cultivation of the plants, the soil was sampled four times from corn and a red clover cultivar and grass. The FYM fertilization rate for which the highest arylsulphatase activity and the content of sulphates were identified was 60 Mg ha-1. An inhibitory effect of high rates (90 and 135 kg N ha-1) of ammonium nitrate on the arylsulphatase activity was also observed. A significant correlation between the content of carbon, nitrogen, and sulphates and the arylsulphatase activity was recorded. The investigation on the effect of combined application of farmyard manure and mineral nitrogen fertilization on the activity of arylsulphatase participating in the sulphur cycling was launched to examine the problem in detail.

  4. Chloroquine Is a Zinc Ionophore

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    Jing Xue; Amanda Moyer; Bing Peng; Jinchang Wu; Hannafon, Bethany N.; Wei-Qun Ding

    2014-01-01

    Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assa...

  5. Chloroquine Phosphate Oral

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    ... as a tablet to take by mouth. For prevention of malaria in adults, one dose is usually taken once ... a day for the next 2 days.For prevention and treatment of malaria in infants and children, the amount of chloroquine ...

  6. Chloroquine is a zinc ionophore.

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    Jing Xue

    Full Text Available Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780. Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.

  7. Chloroquine-induced pruritus

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    Aghahowa S

    2010-01-01

    Full Text Available Chloroquine-induced pruritus remains one of the most common side-effects in the use of chloroquine in the prophylaxis and treatment of uncomplicated malaria before the advent of artemisinin-based combination therapies. It has been reported to vary from a tolerable to intolerable intensity among susceptible individuals resulting in disruption of treatment and development of resistance to the drug thus leading to therapeutic failures as reported. This scourge is quite challenging due to the complex physiologic mechanism that has not been fully elucidated. Factors observed to be responsible in the induction of pruritus such as age, race, heredity, density of parasitaemia; impurities in formulations, plasmodial specie, dosage form and metabolites have been discussed in this review. Efforts to ameliorate this burden have necessitated the use of drugs of diverse pharmacological classes such as antihistamines, corticosteroids and multivitamins either alone or as a combination. This review is to look into the use of chloroquine retrospectively, and consider its re-introduction due to its safety. Efficacy can be attained if the pruritic effect is resolved.

  8. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  9. Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI

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    Uttarilli, Anusha; Ranganath, Prajnya; Jain, S. Jamal Md Nurul; Krishna, Prasad C.; Sinha, Anupam; Verma, Ishwar C.; Phadke, Shubha R.; Puri, Ratna D.; Danda, Sumita; Muranjan, Mamta N.; Jevalikar, Ganesh; Nagarajaram, H. A.; Dalal, Ashwin B.

    2015-01-01

    Background & objectives: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. Methods: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. Results: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. Interpretation & conclusions: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI. PMID:26609033

  10. Effect of chloroquine on human lymphocyte proliferation

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    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    The effect of chloroquine on human blood mononuclear cells was studied. High concentrations of chloroquine in vitro profoundly suppressed the proliferation of mitogen- and antigen-stimulated cells, as indicated by decreased 14C-thymidine incorporation. Lower concentrations of chloroquine increase...

  11. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

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    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  12. Chitosan conjugated chloroquine: proficient to protect the induction of liver apoptosis during malaria.

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    Tripathy, Satyajit; Chattopadhyay, Sourav; Dash, Sandeep Kumar; Chowdhuri, Angshuman Ray; Das, Sabyasachi; Sahu, Sumanta Kumar; Majumdar, Subrata; Roy, Somenath

    2015-03-01

    Chitosan has impelled continuous motion by its unique physicochemical and biological characteristics. In our study, chitosan-tripolyphosphate (CS-TPP) particles was conjugated with an undervalued antimalarial drug, chloroquine to find out the proficiency against ROS mediated caspase activation and apoptosis in liver during Plasmodium berghei NK65 infection. The transmission electron microscopic image illustrated the size range of particle was less than 50 nm and the particle showed the blood compatibility. ROS generation, mitochondrial membrane potential, anti apoptotic and pro apoptotic protein level of CS-TPP conjugated chloroquine treated group revealed that CS-TPP conjugation amplified the protective capability of chloroquine. FACS study by annexin v-FITC and PI staining reveals chloroquine treatment reduces significantly (Pnanoparticles to portray defense possessions against malarial damage.

  13. Determination of chloroquine and monodesethylchloroquine in hair.

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    Viala, A; Deturmeny, E; Aubert, C; Estadieu, M; Durand, A; Cano, J P; Delmont, J

    1983-10-01

    Using thin-layer and gas chromatography and mass spectrometry, chloroquine and its major metabolite (monodesethylchloroquine) were identified in hair samples of numerous patients who received this antimalarial drug for several months. In two patients the amounts of chloroquine were, respectively, 310 and 145 mg/kg hair and those of the monodesethylchloroquine 23 and 11 mg/kg. The respective proportions (93 and 7%) are the same in the two subjects. The chloroquine percentage was near those in the spleen or stomach wall after poisoning. Other metabolites in hair are being identified. Hair analysis may provide a good toxicologic and forensic science complement to the blood, urine, and tissues. It may be useful for the control of chloroquine therapy. PMID:6631371

  14. Chloroquine use improves dengue-related symptoms

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    Marcos Carvalho Borges

    2013-08-01

    Full Text Available Dengue is the most important arboviral disease in the world. As chloroquine, an antimalarial agent, has shown some antiviral effects, this study evaluated its effect in patients with dengue. A randomised, double-blind study was performed by administering chloroquine or placebo for three days to 129 patients with dengue-related symptoms. Of these patients, 37 were confirmed as having dengue and completed the study; in total, 19 dengue patients received chloroquine and 18 received placebo. There was no significant difference in the duration of the disease or the degree and days of fever. However, 12 patients (63% with confirmed dengue reported a substantial decrease in pain intensity and a great improvement in their ability to perform daily activities (p = 0.0004 while on the medication and the symptoms returned immediately after these patients stopped taking the medication. The same effect was not observed in patients with diseases other than dengue. Therefore, this study shows that patients with dengue treated with chloroquine had an improvement in their quality of life and were able to resume their daily activities. However, as chloroquine did not alter the duration of the disease or the intensity and days of fever, further studies are necessary to confirm the clinical effects and to assess the side effects of chloroquine in dengue patients.

  15. Evaluation of Sensitivity of Plasmodium vivax to Chloroquine

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    Nateghpour M

    2007-09-01

    Full Text Available "nBackground: To monitor the current response of P. vivax to chloroquine in South and Southeast Iran."nMethods: The study was undertaken from August 2004 until August 2005 at the Bandar- Abbas, Iranshahr, Nikshahr and Chabahar districts. A total of 195 patients out of 225 parasitologically positive P. vivax cases completed the study .The patients were given a standard 3- day regimen of chloroquine and followed-up clinically and parasitologically accord­ing to the world Health Organization guideline with some modifications. Results of study were addressed as mean of parasite clearance time (MPCT. "nResults: The patients responded to the regimen of chloroquine within 24-120 hours. The MPCTs of P. vivax for Ban­dar- Abbas, Iranshahr, Nikshahr and Chabahar districts were 63.05(±15.37, 56(± 21.7, 70.92 (±6.51 and 58(±14 hours, respectively and for the whole study area (South and South East of Iran was 63.50(±15.84 hours. The results of the whole studied areas indicate that difference of MPCT between male and female patients is marginally significant (P=0.05."nConclusion: Although, parasite clearance time for a number of cases occurred within 96 and 120 hours, no P. vivax para­sites had reappeared in considered patients after day five within 28 days follow- up, reflecting that chloroquine is still an efficacious drug for the treatment of vivax malaria in the studied districts. Higher MPCT in Nikshahr district than the other districts indicating this could be an early sign for reduced susceptibility of the parasite to the drug.

  16. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

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    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  17. Effect of Crocus sativus Stigma (saffron alone or in combination with chloroquine on chloroquine sensitive strain of Plasmodium berghei in mice

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    Pestechian Nader

    2015-10-01

    Full Text Available Introduction: In malaria treatment protocols, treatment failure or drug resistance of synthesized drugs like alkaloids related to quinine, and aminoquinolines are the main problems now. Therefore, discovering efficient drugs or combination therapy of blood schizonticidal drugs with different mechanisms or different targets in the parasite is a crucial effort to solve this problem. In this study, the effectiveness of Crocus sativus Stigma (saffron individually and in combination with chloroquine, was considered against chloroquine–sensitive strain of Plasmodium berghei.Methods: At the first stage, using 4 day suppressive Peter’s test in mice, ED50 and survival times of saffron methanol extract, and its aqueous and ethyl acetate fractions and chloroquine on P. berghei were calculated. Then, based on the toxicity and survival time results, combination therapy was conducted with the best saffron fraction and chloroquine against the parasite.Results: The saffron extract, aqueous and ethyl acetate fractions resulted in suppression of parasitemia with ED50 values of 587.0 ± 78.7, 323.7 ± 37.2, and 508.7 ± 35.6 mg/kg, respectively. Combination of ethyl acetate fraction with chloroquine, potentiated the antimalarial property and the survived percent of the treated mice on days 7, 14, and 28 significantly more than chloroquine or ethyl acetate fraction alone.Conclusion: Saffron and its fractions individually can be effective in reducing the parasitemia in mice. The outcome of combination of ethyl acetate fraction with chloroquine on the mice showed synergistic effect on the chloroquine–sensitive strain of parasite.

  18. A Case Report of Suicide with Chloroquine Overdose and Review of Literature

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    Maryam Hosseini

    2016-09-01

    Full Text Available Background & Objective: Suicide is considered as the tenth cause of death worldwide. There are several suicide reports consist in the use of certain unusual drugs, such as chloroquine. Case report: The cadaver of a 25-year-old single woman was found dead in her home and with suspect to using toxins or drugs was brought to Fars Province Forensic administration. She had history of psychiatric problems for which had referred to psychologist several times. Results: After the autopsy, there was no observation of pathologic lesions in her samples of liver, kidney, or heart. In bile samples, using Thin Layer Chromatography (TLC and High Performance Liquid Chromatography (HPLC methods, chloroquine was detected. In visceral and gut samples, chloroquine was found using TLC as +4 reactions and it was confirmed by HPLC and Gas Chromatography Mass Spectrometry (GC-MS. After examining all the aspects, eventually chloroquine overdose and its complications was determined as the cause of the death. Conclusion: Due to the high incidence of suicide in depressed patients and according to family and previous positive experience, preventive strategies based on the recognition and the treatment of depressed patients and also teaching the families to diagnose the illness in addition to the limitation of the free access to chloroquine and similar drugs is suggested to reduce overdose complications or suicide.

  19. Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine

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    Warhurst David C

    2003-09-01

    Full Text Available Abstract Background Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. Methods Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. Results and conclusions The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.

  20. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

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    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  1. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

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    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  2. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve;

    2016-01-01

    BACKGROUND:  Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed to...

  3. Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers

    DEFF Research Database (Denmark)

    Petersen, E; Ronne, T; Ronn, A;

    2000-01-01

    BACKGROUND: The aim of the study was to provide data on the relative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and mefloquine. METHOD: The study was an open, nonrandomized study recording self-reported events in travelers recruited consecutively from...... two travel clinics in Copenhagen, Denmark. The main outcome measures were the relative proportion of travelers reporting particular symptoms in the three prophylaxis groups, compliance, hospitalization and premature termination of the travel. RESULTS: From May 1996 to April 1998 5, 446 travelers were...... included and 4,158 questionnaires (76.3%) returned. Compliance was significantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% in chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plus proguanil, and mefloquine respectively...

  4. Development of in-vitro radiometric assay for the rapid assessment of chloroquine resistant plasmodium vivax

    International Nuclear Information System (INIS)

    Previously, resistance of malaria parasite to chloroquine has been restricted only to Plasmodium falciparum. Recently, there have been many reports of chloroquine-resistant Plasmodium vivax. One of the mechanisms of chloroquine resistance is the decreased uptake of chloroquine or rapid efflux of the drug from the food vacuole of the parasite. In this study, we have measured the rapid efflux of IH-chloroquine in fifty blood samples from patients with P Vivax infection. All 50 patients were hospitalised for 28 days for the standard treatment with chloroquine. It was found that seven patients who did not respond to the standard regimen of chloroquine have parasites with rapid effluxes of IH-chloroquine. Since rapid effluxes of IH-chloroquine in the resistant parasites showed strong correlation with in vivo 28 days clinical trial, this assay could be used as rapid assessment of chloroquine resistance in patients with P vivax infection

  5. Arylsulphatase in the rhizosphere of plantain Musa AAB and its relation with growth, development and pr Arilsulfatasa en la rizosfera de plátano, Musa AAB y relación con crecimiento, desarrollo y produccion

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    Rao Idupulapati M

    2006-09-01

    Full Text Available

    Arylsulphatase in the rhizosphere of plantain Musa AAB and its relation with growth, development and production. In a plantain crop (Musa AAB of the Central coffee growing zone of Colombia, arylsulphatase activity in a Pachic Melanudand Medial Isotermic soil under three agronomic management systems during 18 months was measured. Measurements were done at 6, 12 and 18 months in four depths, 0-5, 5-10, 10-20, 20-30 cm. The highest arylsulphatase activity (60% was found in the first 10 cm, with a decreasing in depth. Statical analysis did not show significant differences among the three plant ages. Arylsulphatase activity was found between 164 µmol g-1 min-1 and 319 µmol g-1 min-1. The lowest activity was found in the rhizosphere of plants with 12 months of age (flowering under chemical management. Arylsulphatase activity showed very significant correlation with Biomass-C and with Mg in soil, number of leaf and the plantain bunch weight.

    Key words: Enzymic activity-arylsulphatase, andisol, Musa ABB

    En la zona central cafetera de Colombia, en un suelo Pachic Melanudands medial isotérmico, se midió la actividad de arilsulfatasa en rizosfera de plátano Musa AAB, en tres sistemas de manejo agronómico (químico o convencional, tradicional y ecológico, cuatro profundidades (0-5, 5-10, 10-20 y 20-30 cm y tres edades de cultivo (6 meses – diferenciación floral, 12 meses – floración, 18 meses - cosecha. La mayor actividad (60% se encontró en los primeros 10 cm., y disminuyó a medida que se profundizó en el perfil del suelo. El análisis estadístico no mostró diferencias significativas entre los tres manejos o entre edades de planta. La actividad de arilsulfatasa se encontró entre 164 µ mol g-1 min-1 y 319 µ

  6. Hair analysis of an unusual case of Chloroquine intoxication.

    Science.gov (United States)

    Imran, Muhammad; Ashiq, Muhammad Zar; Shafi, Humera; Usman, Hafiz Faisal; Wattoo, Sardar Ali; Sarwar, Muhammad; Tahir, Muhammad Ashraf

    2016-03-01

    A dead body of middle aged man was exhumed from 6.5 month earth-grave. Autopsy findings were non-specific as the body was completely putrefied. Deceased's scalp hair and kidney was sent for toxicological analysis. Hair sample (50mg) was incubated with 1M NaOH (2 ml). Chloroquine was detected in hair and kidney during basic drug screen performed on GC/MS. For confirmation and quantitation, chloroquine was extracted using Hypersep verify CX SPE cartridges while mass detector was operated in SIM mode using the ions of m/z 245.0, 290.1, 319.0 for chloroquine while ions of m/z 260 and 455 were monitored for nalorphine (internal standard). Chloroquine was present in high concentration in hair (211 ng/mg) as well as in kidney (37.3mg/kg). Moreover, chloroquine was not detected in the wash solvents, suggesting ingestion of the drug rather than an external contamination of hair. These findings strongly suggested the acute exposure of higher doses of chloroquine to the deceased before death. PMID:26980246

  7. Chloroquine mediated modulation of Anopheles gambiae gene expression.

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    Patrícia Abrantes

    Full Text Available BACKGROUND: Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.

  8. Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

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    Aline Correa de Carvalho

    2013-01-01

    Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

  9. Chloroquine is grossly overdosed and overused but well tolerated in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2009-01-01

    High chloroquine doses are commonly prescribed in Guinea-Bissau. Double dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed and it is not known if the high doses prescribed in Guinea-Bissau are...... recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations were measured in whole blood. The median total chloroquine dose prescribed and that reportedly taken was 81 and 77 mgkg(-1) respectively. The total dose was usually split into 2-3 daily doses of 6.......6 mgkg(-1) each. These were taken unsupervised for median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50mgkg(-1)) of chloroquine was taken. Only 3/102 children had P. falciparum in the...

  10. In vivo confocal microscopy in chloroquine-induced keratopathy

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    Iacopo Paladini

    2013-01-01

    Full Text Available In vivo confocal microscopy is becoming a mandatory examination to study corneal abnormalities such as drug deposits in systemic disease. A female diagnosed with fibromyalgia on systemic chloroquine for 9 months presented for an ophthalmic examination. Confocal microscopy was performed using the Confoscan 4 (Nidek Co. Ltd., Gamagori, Japan and multiple highly reflective deposits in the epithelial basal cells were found, that were consistent with choloquine. Deposits were also present in the wing cell layer. In the anterior stroma these deposits were rare. Atypically shaped and branched nerves were also present in the anterior stroma. Corneal deposits of chloroquine can be evaluated by confocal microscopy. Confocal microscopy provides information on corneal metabolism and physiology. Chloroquine keratopathy can affect the anterior stroma in addition to the epithelium.

  11. An investigation into the suitability of amidated pectin hydrogel beads as a delivery matrix for chloroquine.

    Science.gov (United States)

    Munjeri, O; Hodza, P; Osim, E E; Musabayane, C T

    1998-08-01

    The aim of the present study was to delay the release of chloroquine to distal parts of the gastrointestinal tract by using a multiparticulate hydrogel formulation. Amidated pectin chloroquine beads (PC) with varying pectin-to-chloroquine ratios (PC) w/w loadings of 4:1, 2:1, and 1:1 in the dried beads were prepared by the gelation of drug-loaded pectin solutions in the presence of calcium. In vitro release studies of chloroquine from pectin-chloroquine hydrogel beads and chloroquine diphosphate powder were carried out in simulated gastric and intestinal fluids. The total release of the entrapped chloroquine from the hydrogel beads was achieved between 4 and 7 h in simulated intestinal fluid, but total release was not achieved in simulated gastric fluid. However, total release from chloroquine diphosphate powder was achieved by 1.5 and 2 h in gastric and intestinal fluids, respectively. The plasma pharmacokinetics of chloroquine from pectin hydrogel beads and chloroquine diphosphate solution following single or repeated dosing were compared in male Sprague-Dawley rats over a period of 60 h. Oral administration of the hyrogel beads to rats produced maximum plasma concentrations by 7 h, but highest plasma concentrations following chloroquine solution administration were observed by 2 h. The dissolution data and appearance of significant plasma concentrations of chloroquine 2 to 4 h after oral administration suggests release in duodenum, jejunum, or ileum.

  12. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    Energy Technology Data Exchange (ETDEWEB)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

    2002-09-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

  13. Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine

    DEFF Research Database (Denmark)

    Fogh, S; Schapira, A; Bygbjerg, Ib Christian;

    1988-01-01

    As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared...... chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking...... chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0...

  14. Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine.

    Science.gov (United States)

    Grundmann, M; Bayer, A

    1976-01-01

    White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.

  15. Enhancement of naked FIX minigene expression by chloroquine in mice

    Institute of Scientific and Technical Information of China (English)

    Hong-yan CHEN; Huan-zhang ZHU; Bin LU; Xuan XU; Ji-hua YAO; Qi SHEN; Jing-lun XUE

    2004-01-01

    AIM: To study the effect of chloroquine on the expression of human clotting factor IX (hFIX) in mice. METHODS:Hydrodynamics-based naked DNA plasmid administration was performed by tail vein injection of 10 μg of pCMVhFIX and chloroquine (0, 100, 200, and 500 μmol/L) in 2.2 mL of Ringer' solution within 6-7 s, the level and stability of hFIX expression, liver damage and toxicity were then examined. RESULTS: The maximum expression of hFIX level was 4.4±-1.8 mg/L at 8 h after injection, 9.7±1.6 mg/L at 24 h only existed in 200 μmol/L chloroquinetreated animals, which is 3-4 fold higher than that of control (P<0.01). There is no significant difference observed among all the treated groups, 3 d later. Transaminase level and liver histological study showed the damage of liver was not related to chloroquine (P>0.05). CONCLUSION: Chloroquine can enhance and sustain exogenous gene expression in vivo without side effect under our experimental conditions.

  16. In vitro evaluation of marketed antimalarial chloroquine phosphate tablets

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    Amit K. Patel, Bhupendra G. Prajapati, Rubina S. Moria & Chhaganbhai N. Patel

    2005-12-01

    Full Text Available Background & objectives: The aim of the present study is to investigate the physicochemicalequivalence of seven brands of tablets containing chloroquine phosphate, an antimalarial purchasedfrom different retail pharmacy outlets.Methods: The quality and physicochemical equivalence of seven different brands of chloroquinephosphate tablets were assessed. The assessment included the evaluation of uniformity of weight,friability, crushing strength, disintegration and dissolution tests as well as chemical assay of thetablets.Results: All the seven brands of the tablets passed the British Pharmacopoeia (BP standards foruniformity of weight, disintegration and crushing strength. One of seven brands failed the friabilitytest. One of the brands did not comply with the standard assay of content of active ingredients.Dissolution test passes the pharmacopoeial standards for chloroquine phosphate tablets. There wereno significant differences in the amounts of chloroquine phosphate released from the different brands.Interpretation & conclusion: Out of the seven brands of anti-malarial chloroquine phosphate tabletsonly one brand fails to meet BP quality specifications which shows constant market monitoring ofnew products to ascertain their equivalency to pharmacopoeial standards.

  17. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations.

    Science.gov (United States)

    White, N J; Miller, K D; Churchill, F C; Berry, C; Brown, J; Williams, S B; Greenwood, B M

    1988-12-01

    Although empirical regimens of parenteral chloroquine have been used extensively to treat severe malaria for 40 years, recent recommendations state that parenteral chloroquine should no longer be used because of potential toxicity. We studied prospectively the pharmacokinetics and toxicity of seven chloroquine regimens in 58 Gambian children with severe chloroquine-sensitive falciparum malaria. In all regimens the total cumulative dose was 25 mg of chloroquine base per kilogram of body weight. Chloroquine was rapidly absorbed after either intramuscular or subcutaneous administration (5 mg of base per kilogram every 12 hours), producing high peak blood concentrations but transient hypotension in 5 of 18 patients (28 percent). Intermittent intravenous infusion (5 mg of base per kilogram over 4 hours, repeated every 12 hours) also produced wide fluctuations in chloroquine levels, suggesting incomplete distribution from a small central compartment. Continuous infusion (0.83 mg of base per kilogram per hour for 30 hours) and smaller, more frequent intramuscular or subcutaneous injections of chloroquine (3.5 mg of base per kilogram every 6 hours) produced smoother blood-concentration profiles with lower early peak levels and no adverse cardiovascular or neurologic effects. Chloroquine given by nasogastric tube (initial dose, 10 mg of base per kilogram) was absorbed well, even in comatose children. We conclude that simple alterations in dosage and frequency of administration can give parenteral chloroquine an acceptable therapeutic ratio and reinstate it as the treatment of choice for severe malaria in areas where chloroquine resistance is not a major problem.

  18. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo.

    Science.gov (United States)

    Takano, Tomomi; Katoh, Yasuichiroh; Doki, Tomoyoshi; Hohdatsu, Tsutomu

    2013-08-01

    Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents.

  19. Impact of Chloroquine on Viral Load in Breast Milk

    Science.gov (United States)

    Semrau, Katherine; Kuhn, Louise; Kasonde, Prisca; Sinkala, Moses; Kankasa, Chipepo; Shutes, Erin; Vwalika, Cheswa; Ghosh, Mrinal; Aldrovandi, Grace; Thea, Donald M.

    2006-01-01

    Summary The anti-malarial agent chloroquine has activity against HIV. We compared the effect of chloroquine (n = 18) to an anti-malarial agent without known anti-HIV-activity, sulfadoxine-pyrimethamine (n = 12), on breast milk HIV RNA levels among HIV-infected breastfeeding women in Zambia. After adjusting for CD4 count and plasma viral load, chloroquine was associated with a trend towards lower levels of HIV RNA in breast milk compared with sulfadoxine-pyrimethamine (P 0.05). Higher breastmilk viral load was also observed among women receiving presumptive treatment = for symptomatic malaria compared with asymptomatic controls and among controls reporting fever in the prior week. Further research is needed to determine the potential role of chloroquine in prevention of HIV transmission through breastfeeding. Impacte de la chloroquine sur la charge virale dans le lait maternelle La chloroquine, agent antimalarique, a une activité contre le VIH. Nous avons comparé l’effet de la chloroquine à celui d’un autre agent antimalarique, la sulfadoxine-pyrimethamine, dont l’activité sur le VIH n’est pas connue, en mesurant les taux d’ARN de VIH dans le lait maternel de femmes allaitantes infectées par le VIH en Zambie. Après ajustement pour les taux de CD4 et la charge virale dans le plasma, la chloroquine comparée à la sulfadoxine pyrimethamine était associée à une tendance vers des teneurs plus bas en ARN de VIH dans le lait maternel (P = 0,05). Des charges virales plus élevées dans le lait maternel étaient aussi observées chez des femmes recevant un traitement présomptif pour des symptômes de malaria par rapport aux contrôles asymptomatiques et par rapport à des contrôles rapportant de la fièvre durant la première semaine. Des études supplémentaires sont nécessaires pour déterminer le rôle potentiel de la chloroquine dans la prévention de la transmission du VIH par l’allaitement maternel. mots clésVIH, malaria, allaitement maternel

  20. Macrofilaricidal effects of chloroquine on adult Onchocerca volvulus by local infiltration of palpable onchocercal nodules

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    Ronald H. Guderian

    1997-12-01

    Full Text Available The macrofilaricidal effects of local infiltration of high concentrations of chloroquine into the capsule of onchocercal nodules on adult worms of Onchocerca volvulus was determined. Six weeks post infiltration, histological examination of single nodules showed all adult worms to be dead. With nodule conglomerates, there was localized action of chloroquine only on the adult worms in the infiltrated nodule, with no diffusion of the drug to adjacent nodules. Chloroquine infiltration of young, recently formed nodules to reduce the adult worm load of infected individuals may be an alternative method to costly nodulectomy.O efeito macrofilaricida da infiltração local, com uma alta concentração de cloroquina, dentro da cápsula do nódulo oncocercótico sobre o verme adulto de Onchocerca volvulus foi determinado. Seis semanas depois da infiltração, estudos histopatológicos de nódulos simple demonstraram todos os vermes adultos mortos. Em conglomerados de nódulos a ação da cloroquina foi só sobre os vermes adultos do nódulo infiltrado, não acontecendo a difusão da droga aos nódulos adjacentes. A infiltração de cloroquina a nódulos novos ou de recente formação reduz a carga de vermes adultos dos indivíduos parasitados e pode ser uma alternativa para os altos custos das nodulectomias.

  1. Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.

    Science.gov (United States)

    Musabayane, C T; Munjeri, O; Matavire, T P

    2003-07-01

    The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.

  2. Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.

    Science.gov (United States)

    Morgan, Michael J; Gamez, Graciela; Menke, Christina; Hernandez, Ariel; Thorburn, Jacqueline; Gidan, Freddi; Staskiewicz, Leah; Morgan, Shellie; Cummings, Christopher; Maycotte, Paola; Thorburn, Andrew

    2014-10-01

    Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.

  3. The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

    Science.gov (United States)

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A.

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

  4. Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine

    OpenAIRE

    Islahudin, Farida; Khozoie, Combiz; Bates, Steven; Ting, Kang-Nee; Pleass, Richard J.; Avery, Simon V.

    2013-01-01

    Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbi...

  5. Chloroquine is grossly under dosed in young children with malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Eksborg, Staffan; Rombo, Lars;

    2014-01-01

    BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy....../l. Adverse events were not age/concentration dependent. CONCLUSIONS: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged

  6. A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

    NARCIS (Netherlands)

    M. Frank; N. Lehners; P.I. Mayengue; J. Gabor; M. Dal-Bianco; D.U. Kombila; G.M. Ngoma; C. Supan; B. Lell; F. Ntoumi; M.P. Grobusch; K. Dietz; P.G. Kremsner

    2011-01-01

    Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant pfcrt allele and its associated chromosomal haplotype were determined be

  7. In vitro inhibition of human influenza A virus replication by chloroquine

    OpenAIRE

    Loh Jin; Chew Janet; Ooi Eng; Chua Robert CS

    2006-01-01

    Abstract Chloroquine is a 9-aminoquinolone with well-known anti-malarial effects. It has biochemical properties that could be applied to inhibit viral replication. We report here that chloroquine is able to inhibit influenza A virus replication, in vitro, and the IC50s of chloroquine against influenza A viruses H1N1 and H3N2 are lower than the plasma concentrations reached during treatment of acute malaria. The potential of chloroquine to be added to the limited range of anti-influenza drugs ...

  8. In vitro inhibition of human influenza A virus replication by chloroquine

    Directory of Open Access Journals (Sweden)

    Loh Jin

    2006-05-01

    Full Text Available Abstract Chloroquine is a 9-aminoquinolone with well-known anti-malarial effects. It has biochemical properties that could be applied to inhibit viral replication. We report here that chloroquine is able to inhibit influenza A virus replication, in vitro, and the IC50s of chloroquine against influenza A viruses H1N1 and H3N2 are lower than the plasma concentrations reached during treatment of acute malaria. The potential of chloroquine to be added to the limited range of anti-influenza drugs should be explored further, particularly since antiviral drugs play a vital role in influenza pandemic preparedness.

  9. Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data

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    Venkatesan Meera

    2011-05-01

    Full Text Available Abstract Background As a result of widespread chloroquine and sulphadoxine-pyrimethamine (SP resistance, 90% of sub-Saharan African countries had adopted policies of artemisinin-based combination therapy (ACT for treatment of uncomplicated malaria by 2007. In Malawi, cessation of chloroquine use was followed by the re-emergence of chloroquine-susceptible malaria. It was expected that introduction of ACT would lead to a return in chloroquine susceptibility throughout Africa, but this has not yet widely occurred. This observation suggests that there is continuing use of ineffective anti-malarials in Africa and that persistent chloroquine-resistant malaria is due to ongoing drug pressure despite national policy changes. Methods To estimate drug use on a national level, 2006-2007 Demographic Health Survey and Multiple Indicator Cluster Survey data from 21 African countries were analysed. Resistance data were compiled by systematic review of the published literature on the prevalence of the Plasmodium falciparum chloroquine resistance transporter polymorphism at codon 76, which causes chloroquine resistance. Results Chloroquine was the most common anti-malarial used according to surveys from 14 of 21 countries analysed, predominantly in West Africa. SP was most commonly reported in two of 21 countries. Among eight countries with longitudinal molecular resistance data, the four countries where the highest proportion of children treated for fever received chloroquine (Uganda, Burkina Faso, Guinea Bissau, and Mali also showed no significant declines in the prevalence of chloroquine-resistant infections. The three countries with low or decreasing chloroquine use among children who reported fever treatment (Malawi, Kenya, and Tanzania had statistically significant declines in the prevalence of chloroquine resistance. Conclusions This study demonstrates that in 2006-2007, chloroquine and SP continued to be used at high rates in many African countries. In

  10. Comparison of chloroquine with artesunate in the treatment of cerebral malaria in Ghanaian children

    DEFF Research Database (Denmark)

    Goka, B Q; Adabayeri, V; Ofori-Adjei, E;

    2001-01-01

    and neurological deficits were documented. There was no difference in mortality rates (chloroquine, 16.7 per cent; artesunate, 21.7 per cent; p = 0.6), neurological deficit at day 14 (chloroquine, 0 per cent; artesunate, 4.3 per cent; p = 0.3), resolution of fever (p = 0.55), and coma recovery time (p = 0...

  11. Chloroquine-Resistant Malaria in Travelers Returning from Haiti after 2010 Earthquake

    OpenAIRE

    Gharbi, Myriam; Dylan R Pillai; Lau, Rachel; Hubert, Véronique; Khairnar, Krishna; Existe, Alexandre; Kendjo, Eric; Dahlström, Sabina; Guérin, Philippe J; Le Bras, Jacques; ,

    2012-01-01

    We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

  12. Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake.

    Science.gov (United States)

    Gharbi, Myriam; Pillai, Dylan R; Lau, Rachel; Hubert, Véronique; Khairnar, Krishna; Existe, Alexandre; Kendjo, Eric; Dahlström, Sabina; Guérin, Philippe J; Le Bras, Jacques

    2012-08-01

    We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance. PMID:22840888

  13. Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species.

    Science.gov (United States)

    Li, Yali; Wan, Zhe; Liu, Wei; Li, Ruoyu

    2015-02-01

    The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.

  14. Chloroquine inhibits accessory cell presentation of soluble natural and synthetic protein antigens

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1984-01-01

    We have studied the in vitro effect of the lysosomotrophic agent, chloroquine, on the presentation of soluble protein antigens by guinea pig accessory cells. Chloroquine inhibited the capacity of antigen-pulsed accessory cells to stimulate proliferation in appropriately primed T cells. The effect...

  15. Optical coherence tomography in a patient with chloroquine-induced maculopathy

    Directory of Open Access Journals (Sweden)

    Korah Sanita

    2008-01-01

    Full Text Available We herein report the optical coherence tomography (OCT findings in a case of chloroquine-induced macular toxicity, which to our knowledge, has so far not been reported. A 53-year-old lady on chloroquine for treatment of rheumatoid arthritis developed decrease in vision 36 months after initiation of the treatment. Clinical examination revealed evidence of retinal pigment epithelial (RPE disturbances. Humphrey field analyzer (HFA, fundus fluorescein angiography (FFA and OCT for retinal thickness and volume measurements at the parafoveal region were done. The HFA revealed bilateral superior paracentral scotomas, FFA demonstrated RPE loss and OCT revealed anatomical evidence of loss of ganglion cell layers, causing marked thinning of the macula and parafoveal region. Parafoveal retinal thickness and volume measurements may be early evidence of chloroquine toxicity, and OCT measurements as a part of chloroquine toxicity screening may be useful in early detection of chloroquine maculopathy.

  16. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  17. Plasmodium falciparum genotypes associated with chloroquine and amodiaquine resistance in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2007-01-01

    infections. The pfcrt 72-76 haplotypes were CVIET and CVMNK. The pfcrt 76T prevalence was 23% at day 0 and 96%, 83% and 100% at recrudescence following treatment with 25 mg/kg and 50 mg/kg of chloroquine and 15 mg/kg of amodiaquine respectively. When treating pfcrt 76T carrying P. falciparum the efficacy...... of 50 mg/kg and 25 mg/kg of chloroquine was 78% and 34% respectively (P = 0.007). The genetic basis of chloroquine resistance is probably the same in Guinea-Bissau as in the rest of Africa. The low pfcrt 76T prevalence suggests that resistance to normal dose chloroquine does not confer a major advantage...... to falciparum in Bissau and could be a result of treatment with high-dose chloroquine....

  18. Chloroquine Transport in Plasmodium falciparum II: Analysis of PfCRT Mediated Drug Transport Using Proteoliposomes and a Fluorescent Chloroquine Probe

    OpenAIRE

    Paguio, Michelle F.; Cabrera, Mynthia; Roepe, Paul D.

    2009-01-01

    Mutations in the PfCRT protein cause chloroquine resistance (CQR) and earlier studies from our laboratory using plasma membrane inside-out vesicles (ISOV) prepared from yeast expressing recombinant PfCRT [Zhang, H., et al. (2004) Biochemistry 43, 8290–8296] suggested that the putative transporter mediates downhill facilitated diffusion of charged chloroquine (CQ). However, more recent experiments with a fluorescent CQ probe (NBD-CQ) presented in the accompanying paper [Cabrera, M., et al. (20...

  19. Use of pre-packaged chloroquine for the home management of presumed malaria in Malagasy children

    Directory of Open Access Journals (Sweden)

    Malvy Denis

    2006-09-01

    Full Text Available Abstract Objective The main objective of this study was to assess the quality of home malaria management with pre-packaged chloroquine in two areas in the Moramanga district of Madagascar. The knowledge, attitude and practices of care providers in terms of home treatment options were evaluated and compared. The availability of treatment options by studying retailers and community-based service providers was also investigated. Methods A cross-sectional investigation in two communities, in the hamlets and villages located close to carers, retailers, community-based service providers and primary health centres was carried out. Results Carers in the two districts were equally well aware of the use of pre-packaged chloroquine. Their first response to the onset of fever was to treat children with this antimalarial drug at home. The dose administered and treatment compliance were entirely satisfactory (100% with pre-packaged chloroquine and rarely satisfactory (1.6% to 4.5% with non pre-packaged chloroquine. In cases of treatment failure, the carers took patients to health centres. Chloroquine was supplied principally by private pharmacies and travelling salesmen selling unpackaged chloroquine tablets. Non pre-packaged chloroquine was the most common drug used at health centres. The frequency of positive rapid malaria tests (P = 0.01 was significantly higher in children treated with non pre-packaged chloroquine (38% than in children treated with pre-packaged chloroquine (1.3%. Conclusion Home malaria management should be improved in Madagascar. Efforts should focus on communication, the training of community-based service providers, access to pre-packaged drugs and the gradual withdrawal of pre-packaged chloroquine and its replacement by pre-packaged artemisinin-based combination therapies.

  20. Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia

    Directory of Open Access Journals (Sweden)

    Laihad Ferdinand

    2010-02-01

    Full Text Available Abstract Background Chloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002. Methods Patients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia. Results 42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16% showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood. The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306. Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65% subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384. Conclusion These findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago.

  1. Trends in chloroquine resistance marker, Pfcrt-K76T mutation ten years after chloroquine withdrawal in Tanzania

    DEFF Research Database (Denmark)

    Mohammed, Asia; Ndaro, Arnold; Kalinga, Akili;

    2013-01-01

    , continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based......Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however...

  2. Color vision loss in patients treated with chloroquine

    Directory of Open Access Journals (Sweden)

    Ventura Dora F.

    2003-01-01

    Full Text Available Patients that make use of chloroquine or hydroxychloroquine, drugs which are frequently administered for treatment of rheumatoid arthritis, lupus erithromatosus or malaria, may suffer alterations in color vision and in contrast sensitivity. The present work evaluates the visual function of these patients in a joint study of the University of São Paulo (USP, in São Paulo, and of the Federal University of Pará (UFPA, in Belém. Thirty two chloroquine user patients without alterations in the eye fundus exam were evaluated in São Paulo (n=10; aged 38 to 71 years; mean=55,8 years and in Belém (n=22; aged 20 to 67; mean=40 years. The prescribed accumulated chloroquine dose was 45 to 430 g (mean=213 g; sd = 152 g for the São Paulo group, and 36 to 540 g (mean=174 g; sd=183 g for the Belém group. Tests were performed monocularly with corrected eye refractive state. Color discrimination was evaluated using the Cambridge Colour Test (CCT: the color discrimination threshold was measured first in the protan, deutan and tritan axes and, in succession, three MacAdam's ellipses were determined. The patient's color vision was also evaluated with color arrangement tests: the Farnsworth-Munsell 100 Hue (FM100, the Farnsworth-Munsell D15, and the Lanthony Desaturated (D15d tests. We also measured the contrast sensitivity for black-and-white sine wave grating of twenty two patients. The results were compared with controls without ophthalmologic or neuro-ophthalmologic pathologies. Twenty four patients presented acquired dyschromatopsia. There were cases of selective loss (11 patients and of diffuse loss (13 patients. Although losses were present in the FM100 there was no correlation between the FM100 error score and the ellipse area measured by the CCT. Moreover, three patients that scored normal in the FM100, failed to reach normal threshold in the CCT. The Lanthony test was less sensitive than the other two tests, since it failed to indicate loss in about

  3. Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Faye, Babacar; Tine, Roger;

    2012-01-01

    Abstract. As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus...... at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal...... with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction...

  4. Pretreatment blood concentrations of chloroquine in patients with malaria infection: relation to response to treatment

    DEFF Research Database (Denmark)

    Quashie, Neils Ben; Akanmori, Bartholomew D; Goka, Bamenla Q;

    2005-01-01

    Resistance of Plasmodium falciparum to chloroquine has been reported in many areas in Ghana. Most of these reports, which are from hospital-based studies, indicate RI and RII rather than RIII type of resistance. Since high pretreatment levels of chloroquine have also been measured in patients...... with malaria infection in Ghana, we hypothesized that the 'added effect' of the pretreatment ingested drug to the full dose given at the hospital may be responsible for the low proportion of RIII type of resistance observed. To ascertain this, pretreatment blood levels of chloroquine were correlated...... and day 0 parasitaemia. Two hundred and seven patients (89.6 per cent) had parasites that were sensitive to chloroquine whilst 24 (10.4 per cent) had resistant parasites. Of the latter group 17, six, and one patients had P. falciparum parasites, which were resistant at RI, RII and RIII levels...

  5. Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection

    OpenAIRE

    Vijaykumar, Theophilus S.; Nath, Avindra; Chauhan, Ashok

    2008-01-01

    We report in this study that minimum productive HIV infection in astrocytes (a predominant cell type in brain and persists for the entire life) occurs through endocytosis. The lysosomotropic agent chloroquine enhanced permissiveness of astrocytes to HIV infection possibly by circumventing degradation of endosome-entrapped viral particles. In particular, chloroquine may promote establishment of a stable long term viral reservoir in astrocytes and may eventually facilitate early onset of neurol...

  6. Binding of chloroquine to ionic micelles: Effect of pH and micellar surface charge

    Energy Technology Data Exchange (ETDEWEB)

    Souza Santos, Marcela de, E-mail: marcelafarmausp77@gmail.com [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Perpétua Freire de Morais Del Lama, Maria, E-mail: mpemdel@fcfrp.usp.br [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Departamento de Química Analítica, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, s/n, Campinas, São Paulo 13083-970 (Brazil); Siuiti Ito, Amando, E-mail: amandosi@ffclrp.usp.br [Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14040-901 (Brazil); and others

    2014-03-15

    The pharmacological action of chloroquine relies on its ability to cross biological membranes in order to accumulate inside lysosomes. The present work aimed at understanding the basis for the interaction between different chloroquine species and ionic micelles of opposite charges, the latter used as a simple membrane model. The sensitivity of absorbance and fluorescence of chloroquine to changes in its local environment was used to probe its interaction with cetyltrimethylammonium micelles presenting bromide (CTAB) and sulfate (CTAS) as counterions, in addition to dodecyl sulfate micelles bearing sodium (SDS) and tetramethylammonium (TMADS) counterions. Counterion exchange was shown to have little effect on drug–micelle interaction. Chloroquine first dissociation constant (pKa{sub 1}) shifted to opposite directions when anionic and cationic micelles were compared. Chloroquine binding constants (K{sub b}) revealed that electrostatic forces mediate charged drug–micelle association, whereas hydrophobic interactions allowed neutral chloroquine to associate with anionic and cationic micelles. Fluorescence quenching studies indicated that monoprotonated chloroquine is inserted deeper into the micelle surface of anionic micelles than its neutral form, the latter being less exposed to the aqueous phase when associated with cationic over anionic assemblies. The findings provide further evidence that chloroquine–micelle interaction is driven by a tight interplay between the drug form and the micellar surface charge, which can have a major effect on the drug biological activity. -- Highlights: • Chloroquine (CQ) pKa{sub 1} increased for SDS micelles and decreased for CTAB micelles. • CQ is solubilized to the surface of both CTAB and SDS micelles. • Monoprotonated CQ is buried deeper into SDS micelles than neutral CQ. • Neutral CQ is less exposed to aqueous phase in CTAB over SDS micelles. • Local pH and micellar surface charge mediate interaction of CQ with

  7. Antimalarial activity of Ageratum conyzoides in combination with chloroquine and artesunate

    Institute of Scientific and Technical Information of China (English)

    Ukwe Chinwe V; Ekwunife Obinna I; Epueke Ebele A; Ubaka Chukwuemeka M

    2010-01-01

    Objective: To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides (A. conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice. Methods: Using malaria (Plasmodium berghei) infected albino mice of both sexes, aqueous extracts of A. conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity, respectively. Four-day suppressive test and Rane's curative test were carried out. Results: Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations. Suppressive activities of both extract-drug combinations were greater than the individual drugs alone. Extract-chloroquine (100:5) produced the highest suppressive effect (98% suppression). Curative tests showed absolute survival in two extract-drug combinations. Two extract-drug combinations produced higher curative effects than the individual drugs alone. The highest dose combinations of extract-chloroquine (100:5) and extract-artesunate (100:5) produced absolute parasitemia clearance (cure) in the infected mice. Conclusions: The study indicated that aqueous extract of A. conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice. It contributes a lot in the malaria endemic and poverty stricken tropics.

  8. Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Schmidt, Berit Aydin; Lebbad, Marianne;

    2007-01-01

    and other genetic polymorphisms in samples from 1992, 1993, 1995, 2004 and 2005. We have also monitored drug prescriptions for febrile illnesses. The mean proportion of in vitro tests indicating chloroquine resistance was 33% (range 14-54%) with the exception of an outlying value year 2000. The proportion...... of chloroquine resistant P. falciparum detected by in vitro testing did not increase over time. Pfcrt 76T was associated with chloroquine resistance but pfmdr1 86Y was not. The mean pfcrt 76T prevalence varied between 13% and 38%. The prevalence of SNPs at Pfcrt positions 76, 271, 326 and pfmdr1 position 86 did...... of chloroquine resistant P. falciparum has not gradually increased between 1990 and 2005 in Guinea-Bissau. Chloroquine is commonly prescribed at more than double the normal dose in Guinea Bissau. It has previously been hypothesized that treatment with high doses of chloroquine may be effective. We discuss...

  9. Maculopatia tóxica por cloroquina Chloroquine toxic maculopathy

    Directory of Open Access Journals (Sweden)

    Nikias Alves da Silva

    2009-06-01

    Full Text Available O fosfato de cloroquina é uma droga largamente utilizada no tratamento de doenças crônicas de autoagressão, mais comumente no controle da artrite reumatóide, do lupus eritematoso discóide ou disseminado, da porfiria cutânea, da urticária solar e outras afecções dermatológicas. Embora a incidência de toxicidade retiniana por esta droga seja baixa, mesmo com o emprego da dose máxima recomendada, sua ocorrência tem grande relevância por acometer a região macular com importante e irreversível comprometimento visual. Trata-se no presente caso de uma paciente de 44 anos, portadora de artrite reumatóide há 19 anos, que fez uso de fosfato de cloroquina na dose de 250 mg/dia durante dois períodos de 4 e 3 anos, intercalados por um período de 8 anos em que usou methotrexate. Ao final do segundo período de uso da cloroquina, foi observada a maculopatia, a partir de quando a droga foi definitivamente substituída por methotrexate e prednisona. Por seu caráter típico e conspícuo, a maculopatia em questão se presta muito bem para ilustrar os achados dos principais métodos propedêuticos que devem ser empregados para caracterizá-la, inclusive a tomografia de coerência óptica.Chloroquine phosphate is widely used for the treatment of chronic autoimune diseases, most commonly rheumatoid arthritis, discoid or disseminated lupus erythematous, light sensitivity eruptions as well as other dermatologic affections. Although the incidence of retinal toxicity by this drug is low even with the maximally recomended dose, its occurrence is relevant because it damages the macula with an important and irreversible visual impairment. A 44-year-old white female patient who had suffered from rheumatoid arthritis for about 19 years had been under treatment with chloroquine phosphate in the daily dose of 250 mg during two periods of 4 and 3 years, intercalated by an 8-year period of methotrexate usage. At the end of the 3-year period, a maculopathy

  10. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Lim Yiting [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hedayati, Mohammad; Merchant, Akil A.; Zhang Yonggang; Yu, Hsiang-Hsuan M. [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Kastan, Michael B. [Department of Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina (United States); Matsui, William, E-mail: matsuwi@jhmi.edu [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); DeWeese, Theodore L., E-mail: deweete@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2012-11-01

    Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 {mu}g per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection

  11. Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum.

    Science.gov (United States)

    Joubert, Jacques; Kapp, Erika; Taylor, Dale; Smith, Peter J; Malan, Sarel F

    2016-02-15

    Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 μM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 μM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 μM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 μM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents. PMID:26832222

  12. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    International Nuclear Information System (INIS)

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy

  13. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ratikan, Josephine Anna [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Sayre, James William [Public Health Biostatistics/Radiology at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Schaue, Dörthe, E-mail: dschaue@mednet.ucla.edu [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States)

    2013-11-15

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy.

  14. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.

  15. Apoptosis of erythrocytic stage parasites of Plasmodium berghei chloroquine-resistant strain

    Institute of Scientific and Technical Information of China (English)

    CHEN Ke-qiang; SONG Guan-hong

    2002-01-01

    Objective: To explore the characteristics of crisis state at erythrocytic stage of Plasmodium berghei chloroquine-resistant (RC) strain. Methods: Agarose electrophoresis, optical and transmission electron microscopes were used. Patterns of genomic DNA structures and ultra-structures of the erythrocytic parasites were observed in ICA mice (infected with the RC strain) during rising and declining of parasitemia. Results: During the declining parasitemia, the erythrocytic stage parasites of the RC strain showed round or oval appearance with intact plasma membrane and shrank nuclei with no metabolic window, mitochondria or other membranaceous structures. Their DNA electrophoretogram revealed a ladder pattern which evidently differed from the parasites of the RC strain in the rising parasitemia and the chloroquine-sensitive (N) strain.Conclusion: The crisis state of the erythrocytic stage parasites of the P. berghei chloroquine-resistant (RC)strain is characterized by apoptosis.

  16. EFFECT OF SINGLE DOSE OF MINOCYCLINE ON A CHLOROQUINE RESISTANT FALCIPARUM INFECTION FROM BALIKPAPAN, KALIMANTAN

    Directory of Open Access Journals (Sweden)

    J. Verdrager

    2012-09-01

    Full Text Available Selain 3 kasus P. falciparum yang resistent terhadap chloroquine dari Samarinda (Verdrager & Arwati, 1974 baru-baru ini ditemukan lagi satu kasus juga dari Kalimantan Timur, tetapi dari daerah yang lain (Balikpapan. Terhadap kasus yang terakhir ini dilaksanakan sensitivity test sesuai dengan standar WHO. Disamping test tersebut, kepada penderita diberikan pula sensitivity test dengan 300 mg minocycline secara single dose. Minocycline yang merupakan derivat dari tetracyclin mempunyai khasiat anti malaria. Pengobatan radical dapat dicapai (pada 9 penderita sukarela yang menderita malaria strain tdari Vietnam sesudah 7 hari pengobatan. Dengan pemberian 300 mg minocycline base secara single dose, bentuk asexual dari parasite menghilang untuk jangka waktu 2 minggu. Effek ini sama dengan effek pemberian 1.500 mg chloroquine base, hanya hilangnya parasit bentuk asexual lebih lambat. Pemberian pengobatan dengan minocycline dengan jangka yang lebih lama sebagai yang dikemukakan oleh WHO (1975 mungkin dapat mengobati radikal strain P. falciparum yang resistent terhadap chloroquine.

  17. RESPONSE OF FALCIPARUM MALARIA TO A STANDARD REGIMEN OF CHLOROQUINE IN JAYAPURA, IRIAN JAYA

    Directory of Open Access Journals (Sweden)

    J. Verdrager

    2012-09-01

    Full Text Available Untuk pertama kalinya di Indonesia, resistensi chloroquine terhadap Plasmodium falciparum telah dilaporkan oleh J. Verdrager dan Arwati pada tahun 1974. Distribusi yang pasti tentang adanya resistensi chloroquine terhadap P. falciparum di Asia Tenggara, khususnya di Indonesia, belumlah begitu jelas. Akan tetapi kelihatannya resistensi ini terdapat di daerah-daerah dimana A. balabacensis sebagai vector. Faktor-faktor lain yang mempengaruhi resistensi ini ialah intensitas transmisi dan penggunaan obat-obat anti malaria yang meluas, terutama pada penduduk yang tak mempunyai kekebalan. Keadaan seperti digambarkan diatas terutama tentang intensitas transmisi yang cukup tinggi terdapat di Irian Jaya dimana vector utama adalah A. punctulatus group. Dari 35 penderita yang di-follow-up, diperoleh 7 orang yang resisten tingkat RI. Seorang diantaranya timbul bentuk asexual dari parasit pada hari ke-9, dan ke-enam lainnya pada hari ke-21 setelah makan obat chloroquine dengan dosis sesuai dengan standard WHO.

  18. Chloroquine resistance and Plasmodium falciparum in Punjab, Pakistan during 2000-2001.

    Science.gov (United States)

    Rana, Muhammad Saleem; Tanveer, Akhtar

    2004-06-01

    During the years 2000-2001, the rural populations of 5 districts in Punjab were examined for malarial parasites. The incidence of Plasmodium falciparum was more than double (8.98%) that of P. vivax (4.06%). The incidence was higher among male subjects (53.5%) than females (46.9%). The largest number of infected male subjects was found in Sheikhupura district (77.78%). Chloroquine resistance was only checked in the subjects harboring P. falciparum, using in vivo techniques. Overall chloroquine sensitivity was 63.8%. Overall frequency of chloroquine resistance in the 5 Punjabi districts was 35%, with 30.6% RI and 4.4% RII. It is important that RIII was not found in the present study. Among the five districts, maximum RI (35.1%) and RII (5.4%) were noted in Multan. By age, maximum chloroquine resistance was noted in the 1-5 year age group (ie RI, 41%; RII 8%). A similar RI value (41%) was noted for the 6-14 age group, but with a low RII (3%) value. Although, the present finding is an outcome of a survey conducted in only 5 districts of Punjab, it reflects an alarming situation, as not only RI and RII resistance against chloroquine is increasing, but at the same time the incidence of P. falciparum is increasing two-fold that of P. vivax. The findings warrant that top priority be given to determining the exact status of chloroquine resistance among P. falciparum in this region, which is now hosting a heavy influx of refugees from Afghanistan, a country endemic for P. falciparum. PMID:15691126

  19. Sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in Nigerian children.

    OpenAIRE

    Ekanem, O. J.; Weisfeld, J. S.; Salako, L A; Nahlen, B. L.; Ezedinachi, E. N.; Walker, O.; Breman, J. G.; Laoye, O. J.; Hedberg, K.

    1990-01-01

    The in vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine was evaluated in children under 5 years of age in two areas of southern Nigeria in 1987. A modification of the WHO Standard Field and Extended Tests (in vivo) was used, with follow-up on days, 2, 3, 7, and 14 after treatment with 25 mg chloroquine per kg body weight given over 3 days, or with standard doses of sulfadoxine/pyrimethamine. Clinical and parasitological evaluations were performed. At Igbo...

  20. Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay.

    Directory of Open Access Journals (Sweden)

    Cheryl C Y Loh

    Full Text Available Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.

  1. Distribution pattern of Plasmodium falciparum chloroquine transporter (pfcrt) gene haplotypes in Sri Lanka 1996-2006

    DEFF Research Database (Denmark)

    Zhang, Jenny J; Senaratne, Tharanga N; Daniels, Rachel;

    2011-01-01

    Abstract. Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72...

  2. Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Coutaux, A F; Mooney, J. J.; Wirth, D. F.

    1994-01-01

    Chloroquine resistance in Plasmodium falciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.

  3. Comparative efficacy of chloroquine and sulphadoxine - pyrimethamine in pregnant women and children: a meta-analysis

    NARCIS (Netherlands)

    G.C. Kalanda; J. Hill; F.H. Verhoeff; B.J. Brabin

    2006-01-01

    Objective: To compare the efficacy of chloroquine and sulphadoxine-pyremethamine against Plasmodium falciparum infection in pregnant women and in children from the same endemic areas of Africa, with the aim of determining the level of correspondence in efficacy determinations in these two risk group

  4. Assessment of therapeutic efficacy of chloroquine and sulphadoxine-pyrimethamine in uncomplicated falciparum malaria

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    Sukla Biswas, Neena Valecha, Prajesh K. Tyagi, Shobhan Phookan, Vas Dev ,Surya K. Sharma & Sarala K. Subbarao

    2003-09-01

    Full Text Available A standardised protocol has been developed by World Health Organization (CDS/RBM/2002 toassess the efficacy of common antimalarials in the treatment of clinically manifested infection withuncomplicated P. falciparum malaria for areas with low to moderate transmission. The therapeuticefficacy protocol is based on clinical and parasitological responses of the patients and it has thepurpose of determining the practical efficacy of the drug regimen in study areas with the ultimateobjective of ascertaining its continued usefulness or the necessity for replacing it in the routinetreatment. Present study has been conducted at seven sites—Kathiatali and Simonabasti of DistrictNowgaon, Assam; Sonapur and Boko of District Kamrup, Assam; Keonjhar Town, Padampur andBasudebpur of District Keonjhar, Orissa. In order to reduce the patient recruitment time, health centreclose to well-defined community was identified to conduct the activities at peak malaria seasonby selecting local pockets and organising mobile clinics. Microscopically confirmed cases of P. falciparumwere enrolled according to the criteria for inclusion and exclusion. Treatment with recommendeddrug was given under supervision and a follow-up schedule at various intervals for 28days was maintained. In chloroquine (CQ study areas, wherever patients showed treatment failure,they were treated with second line drug—sulphadoxine-pyrimethamine (SP combination and thenfollowed-up as per study protocol. It was observed that 30% cases showed treatment failure to CQin District Nowgaon, where revised drug policy has already been introduced. In Kamrup district,treatment failure with CQ was found to be less than 25%, which denotes the said regimen is still effective.Almost all the patients from Padampur and Basudebpur of District Keonjhar responded toCQ, treatment failure was noticed only in two patients (3%. The antifolate combination found to befully effective as second line and also as first line

  5. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Science.gov (United States)

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID:27483471

  6. Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Stephanie G Valderramos

    2010-05-01

    Full Text Available Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ, the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, raising questions about the role of host immunity or pharmacokinetics vs. the parasite genetic background in contributing to treatment outcomes. To examine whether the parasite genetic background dictates the degree of mutant pfcrt-mediated CQ resistance, we replaced the wild type pfcrt allele in three CQ-sensitive strains with mutant pfcrt of the 7G8 allelic type prevalent in South America, the Oceanic region and India. Recombinant clones exhibited strain-dependent CQ responses that ranged from high-level resistance to an incremental shift that did not meet CQ resistance criteria. Nonetheless, even in the most susceptible clones, 7G8 mutant pfcrt enabled parasites to tolerate CQ pressure and recrudesce in vitro after treatment with high concentrations of CQ. 7G8 mutant pfcrt was found to significantly impact parasite responses to other antimalarials used in artemisinin-based combination therapies, in a strain-dependent manner. We also report clinical isolates from French Guiana that harbor mutant pfcrt, identical or related to the 7G8 haplotype, and manifest a CQ tolerance phenotype. One isolate, H209, harbored a novel PfCRT C350R mutation and demonstrated reduced quinine and artemisinin susceptibility. Our data: 1 suggest that high-level CQR is a complex biological process dependent on the presence of mutant pfcrt; 2 implicate a role for variant pfcrt alleles in modulating parasite susceptibility to other clinically important antimalarials; and 3 uncover the existence of a phenotype of CQ tolerance in some strains harboring mutant pfcrt.

  7. Chloroquine stimulates Cl- secretion by Ca2+ activated Cl- channels in rat ileum.

    Directory of Open Access Journals (Sweden)

    Ning Yang

    Full Text Available Chloroquine (CQ, a bitter tasting drug widely used in treatment of malaria, is associated gastrointestinal side effects including nausea or diarrhea. In the present study, we investigated the effect of CQ on electrolyte transport in rat ileum using the Ussing chamber technique. The results showed that CQ evoked an increase in short circuit current (ISC in rat ileum at lower concentration (≤5×10(-4 M but induced a decrease at higher concentrations (≥10(-3 M. These responses were not affected by tetrodotoxin (TTX. Other bitter compounds, such as denatoniumbenzoate and quinine, exhibited similar effects. CQ-evoked increase in ISC was partly reduced by amiloride(10(-4 M, a blocker of epithelial Na(+ channels. Furosemide (10(-4 M, an inhibitor of Na(+-K(+-2Cl(- co-transporter, also inhibited the increased ISC response to CQ, whereas another Cl(- channel inhibitor, CFTR(inh-172(10(-5 M, had no effect. Intriguingly, CQ-evoked increases were almost completely abolished by niflumic acid (10(-4 M, a relatively specific Ca(2+-activated Cl(- channel (CaCC inhibitor. Furthermore, other CaCC inhibitors, such as DIDS and NPPB, also exhibited similar effects. CQ-induced increases in ISC were also abolished by thapsigargin(10(-6 M, a Ca(2+ pump inhibitor and in the absence of either Cl(- or Ca(2+ from bathing solutions. Further studies demonstrated that T2R and CaCC-TMEM16A were colocalized in small intestinal epithelial cells and the T2R agonist CQ evoked an increase of intracelluar Ca(2+ in small intestinal epithelial cells. Taken together, these results demonstrate that CQ induces Cl(- secretion in rat ileum through CaCC at low concentrations, suggesting a novel explanation for CQ-associated gastrointestinal side-effects during the treatment of malaria.

  8. Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar.

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    Valérie Andriantsoanirina

    Full Text Available Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1 act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44% appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites 60% of isolates, but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6. The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days. In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important

  9. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    International Nuclear Information System (INIS)

    Highlights: ► Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. ► Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. ► Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. ► Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  10. Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

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    Shailaja B Khobragade

    2013-01-01

    Full Text Available Objectives: To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent. Materials and Methods: In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control or clofilium (3 mg/kg or chloroquine (21 mg/kg for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM or chloroquine (300 μM continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride. Results: In these models, prolongation of repolarization during α1 -adrenoceptor stimulation produced early after depolarization (EAD and Torsade de pointes (TdP. Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo. Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model. Conclusions: The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.

  11. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    OpenAIRE

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K.; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J.; Volkman, Sarah K.; Wirth, Dyann F.; Legrand, Eric; David A Fidock; Neafsey, Daniel E; Musset, Lise

    2015-01-01

    International audience; In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations ...

  12. The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

    OpenAIRE

    Atroosh Wahib M; Al-Mekhlafi Hesham M; Mahdy Mohammed AK; Surin Johari

    2012-01-01

    Abstract Background Malaria is still a public health problem in Malaysia with chloroquine (CQ) being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt) at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr...

  13. COMPARATIVE STUDY OF EFFECTIVENESS AND RESISTANCE PROFILE OF CHLOROQUINE AND SULFADOXINE - PYRIMETHAMINE IN UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN KOLKATA

    Directory of Open Access Journals (Sweden)

    Ayan

    2014-01-01

    Full Text Available Malaria is one of the major public health problems of the country. Factors responsible for re - emergence of malaria in India was due to emergence and spread of chloroquine resistant Plasmodium falciparum strains across the country coupled with steady rise in insecticide resistance of the vector mosquitoes. Very little is known about the drug resistance status of P. falciparum in India. As per National Vector Borne Diseases Control Programme (NVBDCP , chloroquine is the drug of choice for uncomplicated P. falciparum cases and the combination of Artesunate and Sulfadoxine - Pyrimethamine(SP is being used to treat the documented chloroquine resistant uncomplicated cases. To evaluate the comparative effecti veness and resistance profile of Chloroquine vis - à - vis Sulfadoxine - Pyrimethamine (SP in uncomplicated Plasmodium falciparum cases as the first line therapy a study was undertaken at the Malaria Clinic of School of Tropical Medicine , Kolkata during the per iod from July 2008 to January 2009 under Ward no. 44 of Kolkata Municipal Corporation. Following WHO protocol 2003 and WHO guideline 2006 , a total of 100 parasitologically confirmed Plasmodium falciparum cases were recruited as per the recruitment criteria . Among them , 50 patients were given Chloroquine and another 50 patients were given SP. Eight patients were excluded or lost to follow - up during the follow - up period because of failure to follow the protocol .It was observed that in the chloroquine group ou t of 50 patients , 30 (60% showed Adequate Clinical and Parasitological Response (ACPR , 15 (30% had Late Treatment Failure (LTF and remaining 5 (10% were lost during the follow up period (LFU. On the other hand in the SP group out of 50 patients , 46 ( 92% showed ACPR and only one (2% had LTF and 3 patients were LFU. The difference of LTF in Chloroquine and Sulfadoxine - pyrimethamine groups was statistically significant (p value 10% , Sulfadoxine - Pyrimethamine ca n be

  14. Chloroquine Interference with Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent

    Directory of Open Access Journals (Sweden)

    Christian A. Schaer

    2013-01-01

    Full Text Available The CD163 scavenger receptor pathway for Hb:Hp complexes is an essential mechanism of protection against the toxicity of extracellular hemoglobin (Hb, which can accumulate in the vasculature and within tissues during hemolysis. Chloroquine is a lysosomotropic agent, which has been extensively used as an antimalarial drug in the past, before parasite resistance started to limit its efficacy in most parts of the world. More recent use of chloroquine is related to its immunomodulatory activity in patients with autoimmune diseases, which may also involve hemolytic disease components. In this study we examined the effects of chloroquine on the human Hb clearance pathway. For this purpose we developed a new mass-spectrometry-based method to specifically quantify intracellular Hb peptides within the endosomal-lysosomal compartment by single reaction monitoring (SRM. We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1 response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.

  15. Binding Reaction of Hemin with Chloroquine, Quinine and Quinidine in Water-propylene Glycol Mixture

    Institute of Scientific and Technical Information of China (English)

    MAVAKALA,B.K; NLANDU,B.B.; MPIANA,P.T.; GUSHIMANA,Z.Y.; 尉志武

    2003-01-01

    the interaction of hemin with chloroquine,quinine and quinidine was investigated in 50% water-propylene glycol mixture at pH=9,8.1,7.4 and 6.8using a spectrophotometric method.The data could be well fitted into a model consistent with the formation of a 1:1 complex between the reacting partners.In addition,the results indicated that hemin complexed more strongly with quinidine than with chloroquine and quinine,and the binding constants were pH-dependent.Moreover,it was proved that the water-propylene glycol mixture is well suitable to the study of the systems containing hemin and quinolinebased drugs.

  16. Current understanding of the molecular basis of chloroquine-resistance in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Jiang H

    2006-01-01

    Full Text Available Chloroquine (CQ is the most successful antimalarial drug ever discovered. Unfortunately, parasites resistant to the drug eventually emerged after its large scale use and are now widespread. Although great progress in our understanding of the mechanisms of CQ action and CQ resistance (CQR has been achieved over the past two decades, including the identification of the molecules responsible for CQR (e.g., Plasmodium falciparum chloroquine resistant transporter, PfCRT many questions remain unanswered. Here we highlight recent advances in our understanding of the genetics and molecular mechanisms of CQR, with particular emphasis on the role of genes such as pfcrt and pfmdr1 in the resistance to CQ and other drugs. New drug development and applications will undoubtedly benefit from a better understanding of CQR, eventually leading to more effective malaria control measures.

  17. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  18. EFFECT OF CHLOROQUINE ON BLOOD GLUCOSE LEVELS IN PATIENTS WITH NON INSULIN DEPENDENT DIABETES MELLITUS

    OpenAIRE

    H. Mostafavi

    1998-01-01

    77irty six patients with non insulin dependent diabetes mellitus, whose blood sugar was not controlled with maximal doses of oral hypoglycemic agents and did not accept insulin treatment, were selected for this study. The patients were randomly divided into two groups, the treatment group and the control group. The treatment group received oral hypoglycemic agent and chloroquine (150 mg twice daily) and the control group received oral hypoglycemic agent and placebo for a period of six months....

  19. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    OpenAIRE

    Gao MH; Xu YZ; Qiu LY

    2015-01-01

    Menghua Gao,1 Yuzhen Xu,1 Liyan Qiu2,3 1College of Pharmaceutical Sciences, 2Ministry of Education (MOE) Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 3Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was d...

  20. Fundus auto fluorescence and spectral domain ocular coherence tomography in the early detection of chloroquine retinopathy

    Directory of Open Access Journals (Sweden)

    Megan B. Goodman

    2015-03-01

    Full Text Available Purpose: To determine the sensitivity of spectral domain ocular coherence tomography (SD-OCT and fundus auto fluorescence (FAF images as a screening test to detect early changes in the retina prior to the onset of chloroquine retinopathy.Method: The study was conducted using patients taking chloroquine (CQ, referred by the Rheumatology Department to the Ophthalmology Department at Tygerberg Academic Hospital. Group A consisted of 59 patients on CQ for less than 5 years, and Group B consisted of 53 patients on CQ for more than 5 years. A 200 × 200 macula thickness map, 5-line raster SD-OCT on a Carl Zeiss Meditec Cirrus HD-OCT and FAF images on a Carl Zeiss Meditec Visucam 500 were recorded for 223 eyes. Images were reviewed independently, and then those of Groups A and B compared.Results: There were no statistically significant differences between Groups A and B. The criteria included the internal limiting membrane and the retinal pigment epithelium (ILM-RPE thickness, interdigitation zone integrity (p = 0.891, df = 1, χ² = 0.1876, ellipsoid zone integrity (p = 0.095, df = 2, χ² = 4.699 and FAF image irregularities (p = 0.479, df = 1, χ²= 4995978.Conclusion: The inclusion of SD-OCT and FAF as objective tests into the prescribed screening guidelines does not appear to simplify the detection of subclinical injury in patients on chloroquine treatment.

  1. Comparative study of chloroquine and quinine on malaria rodents and their effects on the mouse testis

    Institute of Scientific and Technical Information of China (English)

    Esmail Abolghasemi; Seyed Hassan Moosa-Kazemi; Maryam Davoudi; Ahmad Reisi; Mohammad Taghi Satvat

    2012-01-01

    Objective: To evaluate the effects of quinine and chloroquine against male mice infected withPlasmodium berghei and their adverse effects on the mice testes. Methods: In this study, 48 adult male mice, (20-25 g), aged 8 to 12 weeks were divided into four groups. This study was carried out from December 2009 until May 2010 in the School of Public Health, Tehran University of Medical Sciences. Results: The results showed that 58.33% of mice treated with chloroquine were completely recovered. Parasitemia was 4% on day 8 when compared to that on day 0, whereas it was 9% on day 9. There was no orchitis found in this group. The mortality of mice after exposing to quinine on day 5 was 8.3%, whereas from day 10 to day 14 it was 91.7%. We found 75% orchitis occurred in quinine treated group. There was a significant difference between quinine and chloroquine effects on the parasite and also mice testes (P<0.05). Conclusions: In this study, It can be concluded that male mice have full resistance to the quinine. Quinine does not only make male mice recover completely, but also cause inflammation on mice testicles tissue.

  2. Similar Efficacy and Tolerability of Double-Dose Chloroquine and Artemether-Lumefantrine for Treatment of Plasmodium falciparum Infection in Guinea-Bissau: A Randomized Trial

    OpenAIRE

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia; Blessborn, Daniel; Thoft-Nielsen, Rikke; Björkman, Anders; Rombo, Lars

    2011-01-01

    Background. In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.

  3. No Genetic Bottleneck in Plasmodium falciparum Wild-Type Pfcrt Alleles Reemerging in Hainan Island, China, following High-Level Chloroquine Resistance▿

    OpenAIRE

    Chen, Nanhua; Gao, Qi; Wang, Shanqing; Wang, Guangze; Gatton, Michelle; Cheng, Qin

    2007-01-01

    Chloroquine-resistant Plasmodium falciparum was highly prevalent in Hainan, China, in the 1970s. Twenty-five years after cessation of chloroquine therapy, the prevalence of P. falciparum wild-type Pfcrt alleles has risen to 36% (95% confidence interval, 22.1 to 52.4%). The diverse origins of wild-type alleles indicate that there was no genetic bottleneck caused by high chloroquine resistance.

  4. Chloroquine enhances gefitinib cytotoxicity in gefitinib-resistant nonsmall cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Mei-Chuan Tang

    Full Text Available Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, including gefitinib, are effective for non-small cell lung cancer (NSCLC patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef from PC-9 cells (containing exon 19 deletion EGFR after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3 were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation, indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM. Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p. and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients.

  5. Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells

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    Qi Zhou

    2016-05-01

    Full Text Available Background/Aims: Chloroquine can induce an increase in the cellular uptake of glucose; however, the underlying mechanism is unclear. Methods: In this study, translocation of GLUT4 and intracellular Ca2+ changes were simultaneously observed by confocal microscope in L6 cells stably over-expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM was traced using HA-GLUT4-GFP. Glucose uptake was measured using a cell-based glucose uptake assay. GLUT4 protein was detected by Western blotting and mRNA level was detected by RT-PCR. Results: We found that chloroquine induced significant increases in glucose uptake, glucose transporter GLUT4 translocation to the plasma membrane (GTPM, GLUT4 fusion with the PM, and intracellular Ca2+ in L6 muscle cells. Chloroquine-induced increases of GTPM and intracellular Ca2+ were inhibited by Gallein (Gβγ inhibitor and U73122 (PLC inhibitor. However, 2-APB (IP3R blocker only blocked the increase in intracellular Ca2+ but did not inhibit GTPM increase. These results indicate that chloroquine, via the Gβγ-PLC-IP3-IP3R pathway, induces elevation of Ca2+, and this Ca2+ increase does not play a role in chloroqui-ne-evoked GTPM increase. However, GLUT4 fusion with the PM and glucose uptake were significantly inhibited with BAPTA-AM. This suggests that Ca2+ enhances GLUT4 fusion with the PM resulting in glucose uptake increase. Conclusion: Our data indicate that chloroquine via Gβγ-PLC-IP3-IP3R induces Ca2+ elevation, which in turn promotes GLUT4 fusion with the PM. Moreover, chloroquine can enhance GLUT4 trafficking to the PM. These mechanisms eventually result in glucose uptake increase in control and insulin-resistant L6 cells. These findings suggest that chloroquine might be a potential drug for improving insulin tolerance in diabetic patients.

  6. Preparation and in vitro evaluation of liposomal chloroquine diphosphate loaded by a transmembrane pH-gradient method.

    Science.gov (United States)

    Qiu, Liyan; Jing, Na; Jin, Yi

    2008-09-01

    This study developed an active loading method for encapsulating chloroquine diphosphate (CQ) into liposomes. The effects of different formulation factors on the encapsulation efficiency (EE) and the size of CQ liposomes were investigated. These factors included the internal phase of liposomes, the external phase of liposomes, the ratio of drug to soybean phosphatidylcholine (drug/SPC), the ratio of cholesterol to soybean phosphatidylcholine (Chol/SPC), and the incubation temperature and time. The EE (93%) was obtained when using drug/SPC (1:50 mass ratio), SPC/Chol (1:5 mass ratio) at 0.10 M citrate-sodium citrate buffer (pH 3.6). As 5 mol% methoxypoly(ethylene glycol)(2,000) cholesteryl succinate (CHS-PEG(2000)) or distearoyl phosphatidylethanolamine-poly (ethylene glycol)(2,000) (DSPE-PEG(2000)) was added, the size of particle was reduced and the EE was improved. Freeze-drying with 5% trehalose as a cryoprotectant was carried out to achieve long-term stability. The drug release studies were performed in vitro simulating the desired application conditions, such as physiological fluids (pH 7.4), tumor tissues (pH 6.5) and endosomal compartments (pH 5.5). The release of CQ from the liposomes prepared via remote loading showed the significant pH-sensitivity and retention properties, which favored the application of liposomal CQ at tumor tissues and endosomal compartments.

  7. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

    Directory of Open Access Journals (Sweden)

    Llanos-Cuentas A.

    2001-01-01

    Full Text Available The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (MalaroneTM were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15 or 1,500 mg chloroquine (base over a 3 day period (n=14 (phase 1. The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9 or atovaquone/proguanil as before (n=5 (phase 2. In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] versus 8% [1/13], P<0.0001. In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]. There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

  8. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells

    Science.gov (United States)

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-01-01

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

  9. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells.

    Science.gov (United States)

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-01-01

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells' receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

  10. Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2011-01-01

    In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele...

  11. The Association of K76T Mutation in Pfcrt Gene and Chloroquine Treatment Failure in Uncomplicated Plasmodium falciparum Malaria in a Cohort of Nigerian Children

    Science.gov (United States)

    Umar, R. A.; Hassan, S. W.; Ladan, M. J.; Nma Jiya, M.; Abubakar, M. K.; Nata`Ala, U.

    The aim of this study was to evaluate the association of K76T mutation in Pfcrt gene and chloroquine treatment failure following reports that the efficacy of chloroquine in the treatment of uncomplicated falciparum malaria in Africa is seriously compromised by high levels of drug resistance. The occurrence of mutation on codon 76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene has been associated with development of resistance to chloroquine. We investigated the association of K76T mutation in Pfcrt gene in malaria-infected blood samples from a cohort of Nigerian children with uncomplicated falciparum malaria treated with chloroquine and its association with clinical (in vivo) resistance. The Pfcrt T76 allele was very significantly associated with resistance to chloroquine (Fischer exact test: p = 0.0001). We conclude that K76T mutation in Pfcrt gene is significantly associated with chloroquine resistance and that it could be used as a population marker for chloroquine resistance in this part of the country

  12. Biosynthesis of intestinal microvillar proteins. Surface expression of aminopeptidase N is not affected by chloroquine

    DEFF Research Database (Denmark)

    Danielsen, E M; Sjöström, H; Norén, Ove

    1985-01-01

    The effect of chloroquine on the biosynthesis of pig intestinal aminopeptidase N (EC 3.4.11.2) was studied by labelling with [35S]methionine in organ cultured mucosal explants. The lysosomotropic agent did not alter the molecular size of either the transient or the mature form of the enzyme and d...... no consequence on the intracellular transport of the newly synthesized microvillar enzyme. This suggests that the acidic compartments are not involved in the post-Golgi transport and that this, in turn, probably occurs via a constitutive rather than a regulated pathway....

  13. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras

    Directory of Open Access Journals (Sweden)

    Gustavo A Fontecha

    2014-07-01

    Full Text Available Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt “CVMNK” genotype in codons 72-76.

  14. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras.

    Science.gov (United States)

    Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E

    2014-07-01

    Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.

  15. Effects of chloroquine, mefloquine and quinine on natural killer cell activity in vitro. An analysis of the inhibitory mechanism

    DEFF Research Database (Denmark)

    Pedersen, B K; Bygbjerg, I C; Theander, T G;

    1986-01-01

    Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF...... NK cell enriched populations in a single cell agarose assay, it was shown that the inhibitory effects of mefloquine, but not of chloroquine and quinine were due to an inhibition of the formation of effector/target cell conjugates....

  16. Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites*

    OpenAIRE

    Bellanca, Sebastiano; Summers, Robert L.; Meyrath, Max; Dave, Anurag; Nash, Megan N.; Dittmer, Martin; Sanchez, Cecilia P.; Stein, Wilfred D; Martin, Rowena E.; Lanzer, Michael

    2014-01-01

    Mutations in the “chloroquine resistance transporter” (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports qu...

  17. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    Directory of Open Access Journals (Sweden)

    Gao MH

    2015-10-01

    Full Text Available Menghua Gao,1 Yuzhen Xu,1 Liyan Qiu2,3 1College of Pharmaceutical Sciences, 2Ministry of Education (MOE Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 3Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: A novel composite liposomal system co-encapsulating paclitaxel (PTX with chloroquine phosphate (CQ was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy. Keywords: paclitaxel, chloroquine, liposome, drug resistance, combination therapy

  18. In Vivo Susceptibility of Plasmodium Vivax to Chloroquine in Southeastern Iran

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    S Dittrich

    2012-06-01

    Full Text Available Background: Plasmodium vivax is the predominant species causes of malaria with about 90% total annual reported malaria in Iran. This study conducted to determine the susceptibility of Plasmodium vivax isolates to chloroquine in Sistan and Balochistan Province, southeastern Iran.Methods: A total 270 subjects with symptomatic malaria and confirmed P. vivax infection completed the designed 28-day in vivo study. The thick and thin film blood smears were screened for malaria parasites by microscopy. The nested PCR was applied using the Plasmodium 18 subunit ribosomal ribonu­cleic (Ssr RNA genes for detecting mixed infections and diagnosis of parasites in the samples with low parasite on days 0, 5, 6, 7, and 28. Results: P. vivax was cleared in 15%, 50%, 95%, and 100% of patients on days 1, 2, 3, 4 respectively by microscopy assessment. Six patients were exhibited specific P. vivax band in nested PCR on day 5. No recurrence was observed on days 7, 14 and 28. Mean (±standard deviation parasite clearance time was 2.41 (±0.8 days. Conclusion: P. vivax is still susceptible to chloroquine in Southeatern Iran. This finding is compati­ble with results of neighboring countries Pakistan and Afghanistan.

  19. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  20. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  1. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in Albino and Pigmented Rats

    International Nuclear Information System (INIS)

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine

  2. Emerging Plasmodium vivax resistance to chloroquine in South America: an overview

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    Lígia Antunes Gonçalves

    2014-08-01

    Full Text Available The global emergence of Plasmodium vivax strains resistant to chloroquine (CQ since the late 1980s is complicating the current international efforts for malaria control and elimination. Furthermore, CQ-resistant vivax malaria has already reached an alarming prevalence in Indonesia, East Timor and Papua New Guinea. More recently, in vivo studies have documented CQ-resistant P. vivax infections in Guyana, Peru and Brazil. Here, we summarise the available data on CQ resistance across P. vivax-endemic areas of Latin America by combining published in vivo and in vitro studies. We also review the current knowledge regarding the molecular mechanisms of CQ resistance in P. vivax and the prospects for developing and standardising reliable molecular markers of drug resistance. Finally, we discuss how the Worldwide Antimalarial Resistance Network, an international collaborative effort involving malaria experts from all continents, might contribute to the current regional efforts to map CQ-resistant vivax malaria in South America.

  3. Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

    Science.gov (United States)

    Torres, Rosa Elena Mejia; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A.; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-01-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization—World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras. PMID:23458957

  4. The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine

    Directory of Open Access Journals (Sweden)

    Giovanny Garavito

    2012-09-01

    Full Text Available The effectiveness of methylene blue (MB combined with pyrimethamine (PYR, chloroquine (CQ or quinine (Q was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day or Q (25 mg/kg/day. No synergy was found between MB (15 mg/Kg and CQ (0.75 mg/Kg. Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

  5. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria;

    2014-01-01

    Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs...... as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts...... in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more...

  6. Membrane fusion inducers, chloroquine and spermidine increase lipoplex-mediated gene transfection

    Energy Technology Data Exchange (ETDEWEB)

    Wong-Baeza, Carlos; Bustos, Israel; Serna, Manuel; Tescucano, Alonso; Alcantara-Farfan, Veronica; Ibanez, Miguel [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico); Montanez, Cecilia [Department of Genetics and Molecular Biology, Centre for Research and Advanced Studies (CINVESTAV), IPN, Mexico City 07360 (Mexico); Wong, Carlos [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico); Baeza, Isabel, E-mail: ibaeza@encb.ipn.mx [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico)

    2010-05-28

    Gene transfection into mammalian cells can be achieved with viral and non-viral vectors. Non-viral vectors, such as cationic lipids that form lipoplexes with DNA, are safer and more stable than viral vectors, but their transfection efficiencies are lower. Here we describe that the simultaneous treatment with a membrane fusion inducer (chlorpromazine or procainamide) plus the lysosomotropic agent chloroquine increases lipoplex-mediated gene transfection in human (HEK293 and C-33 A) and rat (PC12) cell lines (up to 9.2-fold), as well as in situ in BALB/c mice spleens and livers (up to 6-fold); and that the polyamine spermidine increases lipoplex-mediated gene transfection and expression in cell cultures. The use of these four drugs provides a novel, safe and relatively inexpensive way to considerably increase lipoplex-mediated gene transfection efficiency.

  7. The pH dependent toxicity and bioaccumulation of chloroquine tested on S. viminalis (basket willow)

    DEFF Research Database (Denmark)

    Rendal, Cecilie; Trapp, Stefan; Legind, Charlotte Nielsen

    2010-01-01

    divalent weak base) on S. viminalis (basket willow). The transpiration of sprouted S. viminalis cuttings was monitored under the exposure of increasing concentrations (1, 10, 20, and 40 mg/L) of chloroquine at pH levels of 6, 7, 8, and 9. Solutions were buffered with phosphate (pH 6 and 7) and TRIS...... (hydroxymethyl) – aminomethane (pH 8 and 9). Concentrations were determined with spectrophotometer. Toxicity was derived from calculations of normalized transpiration over time, and RCF (root concentration factor) values were calculated. Increasing BCF values were found for increasing pH levels, and the toxicity......It is known that the uptake and accumulation of electrolytes is very sensitive to pH owing to the slower diffusion of charged compounds across membranes, and other factors such as the Nernst effect and the ion trap effect. However, the significance of pH to the bioaccumulation of electrolytes has...

  8. Low level genotypic chloroquine resistance near Malawi's northern border with Tanzania.

    Science.gov (United States)

    Bridges, Daniel J; Molyneux, Malcolm; Nkhoma, Standwell

    2009-09-01

    We conducted a prevalence study of mutations in Plasmodium falciparum that are associated with antimalarial drug resistance at a rural site in Karonga near Malawi's northern border with Tanzania. We found a higher prevalence of the key chloroquine resistance-conferring mutation in the pfcrt gene (K76T) at this site in comparison with the prevalence in Blantyre, a city in the south of Malawi, far from an international border (9%vs. 0%; P Malawi was recently reported to be over 50%. Our findings suggest a considerable 'leakage' of parasite antimalarial drug resistance across the border between two countries with different national malaria control policies and with different levels of resistance. Neighbouring countries should consider implementing common regional rather than national malaria treatment policies to prevent the spread of antimalarial drug resistance alleles across their borders.

  9. Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

    Science.gov (United States)

    Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-05-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

  10. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma.

    Science.gov (United States)

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID:26971793

  11. Chloroquine-induced bilateral anterior shoulder dislocation: a unique aetiology for a rare clinical problem.

    Science.gov (United States)

    Martin, Alexander Nicholas; Tsekes, Dimitris; White, William James; Rossouw, Dan

    2016-01-01

    Bilateral anterior shoulder dislocation is a rare clinical entity with few case reports and limited series published in the literature. Bilateral shoulder dislocations are rare and of them, most are posterior. We present a highly unusual case of bilateral, atraumatic, anterior shoulder dislocation with concomitant comminuted greater tuberosity fracture on the right side, secondary to seizure, in a patient without known epilepsy, induced by oral chloroquine medication. We demonstrate the treatment approach that led to a satisfactory clinical outcome, evidenced by radiological union, clinical assessment and Patient Reported Outcome Measure data, following non-operative management of both shoulders. The unusual mechanism for anterior shoulder dislocation, the asymmetric dislocation pattern and peculiar precipitant for the causative seizure all provide interesting learning points from this case. PMID:27005796

  12. Functional characterization of the Plasmodium falciparum chloroquine-resistance transporter (PfCRT in transformed Dictyostelium discoideum vesicles.

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    Janni Papakrivos

    Full Text Available BACKGROUND: Chloroquine (CQ-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQ-resistant (but not CQ-sensitive P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT confer CQR; particularly important among these mutations is the charge-loss substitution K→T at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. METHODOLOGY AND FINDINGS: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRT-transformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K(+ to reverse membrane potential hyperpolarization caused by valinomycin treatment. CONCLUSION: Isolated vesicles from mutant-PfCRT-transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an

  13. Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis : A Randomized Controlled Trial

    NARCIS (Netherlands)

    G.J.H. Baestians (Guido); M.P.A. van Meer (Maurits); A. Scholzen (Anja); J.M. Obiero (Joshua); M. Vatanshenassan (Mansoureh); T. van Grinsven (Tim); B.K.L. Sim (B. Kim Lee); P.F. Billingsley (Peter); E.R. James (Eric); A. Gunasekera (Anusha); E.M. Bijker (Else); G-J. van Gemert (Geert-Jan); M. van de Vegte-Bolmer (Magda); W. Graumans (Wouter); C.C. Hermsen (Cornelus); Q. de Mast (Quirijn); A.J.A.M. van der Ven (André); S.L. Hoffman (Stephen); R.W. Sauerwein (Robert)

    2015-01-01

    markdownabstractImmunization of volunteers under chloroquine prophylaxis by bites of *Plasmodium falciparum* sporozoite (PfSPZ)–infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in

  14. Effects of Chloroquine on GFAP, PCNA and Cyclin D1 in Hippocampus and Cerebral Cortex of Rats with Seizures Induced by Pentylenetetrazole

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shuhua; ZHU Changgeng; LIU Qingying; WANG Wei

    2005-01-01

    The effects of chloroquine on glial fibrillary acidic protein (GFAP), proliferation cell nuclear antigen (PCNA) and Cyclin D1 in hippocampus and cerebral cortex of rats with seizures induced by pentylenetetrazole (PTZ) were observed in the present study. Forty-eight male adult Sprague-Dawley (SD) rats were randomly divided into control group, chloroquine intervening group, and PTZ group. The behavior and electroencephalogram (EEG) were observed and recor ded. GFAP and PCNA were examined with immunohistochemistry. The content of Cyclin D1 in hippocampus and cerebral cortex was inspected with Western blot. The results showed no seizure activity in the control group, severe seizure activity in the PTZ group (Ⅳ-Ⅴ degree), and slight seizure activity ( Ⅰ - Ⅲ degree) in the chloroquine intervening group (P<0. 05). EEG recordings showed no epileptic spikes in the control group, high amplitude with fast frequency in the PTZ group, low-amplitude and slow frequency in the chloroquine intervening group. The expression of GFAP and the positive index of PCNA in the PTZ group were higher than those of control group (P <0.05 and P<0.01, respectively). No differences in GFAP expression and PCNA index were observed between chloroquine intervening and control groups (P>0.05). The content of Cyclin D1 in hippocampus and cerebral cortex was significantly higher in the PTZ group than in control and chloroquine intervening groups (P< 0.05). Therefore, it is considered that chloroquine, by inhibiting the functions and proliferation of glial cells in the hippocampus and cerebral cortex, can alleviate the seizure activities. These results suggest that chloroquine may be an ideal anticonvulsant in preventing and treating epilepsy.

  15. Rapid selection of Plasmodium falciparum chloroquine resistance transporter gene and multidrug resistance gene-1 haplotypes associated with past chloroquine and present artemether-lumefantrine use in Inhambane District, southern Mozambique

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H;

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...

  16. Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Mehlotra, Rajeev K; Mattera, Gabriel; Bockarie, Moses J;

    2008-01-01

    Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also...... different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.......Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also...

  17. Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

    OpenAIRE

    Wurtz, Nathalie; Fall, Bécaye; Pascual, Aurélie; Fall, Mansour; Baret, Eric; Camara, Cheikhou; Nakoulima, Aminata; Diatta, Bakary; Fall, Khadidiatou Ba; Mbaye, Pape Saliou; Diémé, Yaya; Bercion, Raymond; Wade, Boubacar; Pradines, Bruno

    2014-01-01

    The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutat...

  18. In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

    OpenAIRE

    Sahu, Rajnish; Walker, Larry A.; Tekwani, Babu L.

    2014-01-01

    Background Several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics. Methods Tigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falcip...

  19. Effects of chloroquine and cytochalasin B on the infection of cells by Sindbis virus and vesicular stomatitis virus.

    OpenAIRE

    Coombs, K; Mann, E; Edwards, J; Brown, D T

    1981-01-01

    The effects of cytochalasin B and chloroquine on the process of endocytosis of Sindbis virus particles and polystyrene spheres were determined by electron microscopy. The effects of these agents on the process of infection (attachment, penetration, and uncoating) of BHK-21 cells by Sindbis virus and vesicular stomatitis virus were also determined. Cytochalasin B completely blocked ingestion of Sindbis virus particles or latex spheres by BHK cells but had no effect on the ability of Sindbis vi...

  20. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

    OpenAIRE

    Mikus Gerd; Walter-Sack Ingeborg; Jahn Albrecht; Schiek Wolfgang; Rengelshausen Jens; Mansmann Ulrich; Tapsoba Théophile; Witte Steffen; Coulibaly Boubacar; Mandi Germain; Meissner Peter E; Burhenne Jürgen; Riedel Klaus-Dieter; Schirmer R Heiner; Kouyaté Bocar

    2006-01-01

    Abstract The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical ...

  1. Dynamics of pfcrt alleles CVMNK and CVIET in chloroquine-treated Sudanese patients infected with Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Warhurst David C

    2010-03-01

    Full Text Available Abstract Background Parasite resistance to the anti-malarial drug chloroquine is common in eastern Sudan. Dynamic within-host changes in the relative abundance of both sensitive and resistant Plasmodium falciparum parasites were examined in a cohort of chloroquine-treated patients presenting with uncomplicated falciparum malaria, using a novel allele-specific quantitative approach. Methods Treatment outcomes were determined for 93 patients of all ages in a per protocol cohort using a modified 14-day WHO protocol. Parasite DNA samples at days 0, 1, 2, 3, 7 and 14 following treatment were analysed using real-time quantitative PCR methods that distinguished resistant and sensitive genotypes at amino acids 72 - 76 of the pfcrt locus. Results Chloroquine treatment was not efficacious, and of 93 assessable patients, only 10 individuals (10.7%; 95% C.I. 4.34 - 17.2% enjoyed an adequate clinical and parasitological response. Resistant parasites with the haplotype CVIET at codons 72-76 of the pfcrt locus were dominant in the starting population. Chloroquine sensitive parasites with the haplotype CVMNK were detected in 19 individuals prior to treatment (20.43%; 95% C.I. 5.14 - 18.5%. In these patients, CQ treatment rapidly selected CVIET parasites, and this haplotype overwhelmingly dominated the parasite population in each individual by day 2 after treatment. Conclusions Such rapid intra-host selection of particular genotypes after the introduction of drug will cause frequent misidentification of parasite genotypes present in the starting population. This will have a potentially serious confounding effect on clinical trials which employ PCR-corrected estimates of treatment failure, as resistant parasites below the detection threshold in the pre-treatment sample can be erroneously classified as "new" infections during follow-up, over-estimating drug efficacy.

  2. Arguments against Chemoprophylaxis in Areas at Low Risk for Chloroquine-Resistant Plasmodium falciparum.

    Science.gov (United States)

    Armengaud

    1995-03-01

    Chemoprophylaxis of malaria prevents the disease not the infection (suppressive chemoprophylaxis) with "high levels of confusion and low levels of compliance." The magnitude of danger of contracting malaria for travelers varies in several endemic zones. In West Africa, without prophylaxis, malaria is estimated to have an incidence of 1.4% per person per month. In South and Central America, the incidence is 0.05 and 0.01% per month, respectively. In Asia, the transmission and percentage of infection due to Plasmodium falciparum is much lower. The dangers of chemoprophylaxis in an area at low risk for chloroquine resistant P. falciparum are a reality. Incompletely active drugs change clinical manifestations, and changes in clinical manifestations delay the establishment of a correct diagnosis. The rate of adverse events is 15-20%, and hospitalization due to side effects of prophylaxis occurs in one in 10,000 travelers. Neuropsychiatric side effects have been reported with both mefloquine and chloroquine. A false sense of security can hinder a physician practicing in a nonendemic area from thinking of malaria when a traveler returns with fever. To complicate the picture, in many countries, there is an emerging drug resistance in P. falciparum as well as an emerging chloroquine resistance in P. vivax strains (20% in New Guinea and Irian Jaya). In short, no available chemoprophylaxis is free from toxicity, and its efficacy is never 100%. Alternatives to conventional chemoprophylaxis are encouraged in areas of low morbidity of malaria. In areas where P. vivax occurs primarily, and when the risk of serious side effects from chemoprophylaxis outweighs the risk of life threatening P. falciparum infection, there are four alternative strategies.2,3 The first strategy is that the traveler avoid mosquito bites. With a compulsive attitude, a high degree of protection can be realized with the proper use of pyrethrum-impregnated mosquito netting, topical DEET-containing insect

  3. The behavior of chloroquine (a synthesized anti-malaria drug) labeled with 14C in healthy and malarious animals

    International Nuclear Information System (INIS)

    The distribution of 14C labeled chloroquine is identical in healthy and malarious animals. Fixation (by order of intensity) takes place in the liver, spleen, lungs, lacrimal glands, cerebrospinal fluid, bones, thyroid, and intestinal walls. This was confirmed from quantitative studies and demonstrates the traversing of the blood-brain barrier and the intestinal elimination after biliary excretion. Pharmaco-kinetic studies were undertaken with healthy animals and those afflicted with malaria. After a phase, in which the distribution of chloroquine is identical for both types of animal, a more rapid decrease in the blood level is observed with the malarious animals. The leucocytes contained distinctly more of the tracer than the normal or malarious red corpuscles or the blood plasma. Examination of the urinary elimination revealed a mono-exponential function; nevertheless, the urinary elimination was less regular with the malarious rats. This elimination corresponds to the excretion of unchanged chloroquine accompanied by two metabolites. A third metabolite appeared after a delay period. (author)

  4. Sequence and gene expression of chloroquine resistance transporter (pfcrt in the association of in vitro drugs resistance of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Bray Patrick G

    2011-02-01

    Full Text Available Abstract Background Plasmodium falciparum chloroquine resistance (CQR transporter protein (PfCRT is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance. Methods In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis. Results Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed. Conclusion Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt.

  5. Genotyping of chloroquine resistant Plasmodium falciparum in wild caught Anopheles minimus mosquitoes in a malaria endemic area of Assam, India.

    Science.gov (United States)

    Sarma, D K; Mohapatra, P K; Bhattacharyya, D R; Mahanta, J; Prakash, A

    2014-09-01

    We validated the feasibility of using Plasmodium falciparum, the human malaria parasite, DNA present in wild caught vector mosquitoes for the characterization of chloroquine resistance status. House frequenting mosquitoes belonging to Anopheles minimus complex were collected from human dwellings in a malaria endemic area of Assam, Northeast India and DNA was extracted from the head-thorax region of individual mosquitoes. Anopheles minimus complex mosquitoes were identified to species level and screened for the presence of Plasmodium sp. using molecular tools. Nested PCR-RFLP method was used for genotyping of P. falciparum based on K76T mutation in the chloroquine resistance transporter (pfcrt) gene. Three of the 27 wild caught An. minimus mosquitoes were harbouring P. falciparum sporozoites (positivity 11.1%) and all 3 were had 76T mutation in the pfcrt gene, indicating chloroquine resistance. The approach of characterizing antimalarial resistance of malaria parasite in vector mosquitoes can potentially be used as a surveillance tool for monitoring transmission of antimalarial drug resistant parasite strains in the community.

  6. Effects of Low Dose of Ketotifen and Chloroquine Combination on the Ultrastructure of Chloroquine Resistant Strain of Plasmodium Yoelii%低剂量氯喹和酮替酚联合作用下疟原虫的超微结构研究

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    46 inbred NIH mice were infected by chloroquine resistant strain of Plasmodium yoelii. The ultrastructure changes were observed under the administration of ketotifen(10mg· kg- 1· d- 1 ) and chloroquine( 10mg. kg-1 · d- 1 ) combination and one after another respectively. The effect of taking ketotifen and chloroquine combination showed that parasites died rapidly with a few of intermittent membranes and vacuoles. The effect of taking two kinds of drugs one after another showed that there were exceedingly rich membranes, concentric arrangement structures similar to rough endo-reticulum and conspiciously blocking of the formation of food vacuoles.

  7. Identification of pyrimethamine- and chloroquine-resistant Plasmodium falciparum in Africa between 1984 and 1998: genotyping of archive blood samples

    Directory of Open Access Journals (Sweden)

    Saito-Nakano Yumiko

    2011-12-01

    Full Text Available Abstract Background Understanding the geographical distribution of drug resistance of Plasmodium falciparum is important for the effective treatment of malaria. Drug resistance has previously been inferred mainly from records of clinical resistance. However, clinical resistance is not always consistent with the parasite's genetic resistance. Thus, molecular identification of the parasite's drug resistance is required. In Africa, clinical resistance to pyrimethamine (Pyr and chloroquine (CQ was evident before 1980 but few studies investigating the genetic resistance to these drugs were conducted before the late 1990s. In this study, genotyping of genes involved in resistance to Pyr and CQ was performed using archive blood samples from Africa between 1984 and 1998. Methods Parasite DNA was extracted from P. falciparum-infected blood smears collected from travellers returning to Japan from Africa between 1984 and 1998. Genotypes of the dihydrofolate reductase gene (dhfr and CQ-resistance transporter gene (pfcrt were determined by polymerase chain reaction amplification and sequencing. Results Genotyping of dhfr and pfcrt was successful in 59 and 80 samples, respectively. One wild-type and seven mutant dhfr genotypes were identified. Three dhfr genotypes lacking the S108N mutation (NRSI, ICSI, IRSI; amino acids at positions 51, 59, 108, and 164 with mutations underlined were highly prevalent before 1994 but reduced after 1995, accompanied by an increase in genotypes with the S108N mutation. The dhfr IRNI genotype was first identified in Nigeria in 1991 in the present samples, and its frequency gradually increased. However, two double mutants (ICNI and NRNI, the latter of which was exclusively found in West Africa, were more frequent than the IRNI genotype. Only two pfcrt genotypes were found, the wild-type and a Southeast Asian type (CVIET; amino acids at positions 72-76 with mutations underlined. The CVIET genotype was already present as early as

  8. 3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2016-06-01

    Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner. Similar to CQ, the antimalarial activity of 3-iodo-CQ is likely due to its inhibition of β-haematin formation. Interestingly, the presence of non-inhibitory concentrations of 3-iodo-CQ potentiated the antiproliferative activity of CQ against CQ-resistant strains or P. falciparum transfectants expressing wild-type or mutant P. falciparum CQ resistance transporter (PfCRT) (C2(GC03) or C4(Dd2), respectively). These findings demonstrate that halogenation of the third position of 4-aminoquinoline, with a simple one-step reaction from CQ, generates a novel derivative that is active against CQ-sensitive and -resistant P. falciparum, possibly by inhibiting the activity of mutant PfCRT. PMID:27211211

  9. Surface and micellar properties of Chloroquine Diphosphate and its interactions with surfactants and Human Serum Albumin

    International Nuclear Information System (INIS)

    Highlights: ► Free energy of adsorption is more negative than free energy of micellization. ► Shifts in UV/Visible spectra in presence of SDS indicated interaction of CLQ with SDS. ► The decrease in fluorescence intensity of HSA by CLQ shows its binding with HSA. -- Abstract: This manuscript addresses the physicochemical behavior of an antimalarial drug Chloroquine Diphosphate (CLQ) as well as its interaction with anionic surfactants and Human Serum Albumin (HSA). Surface tension and specific conductivity were employed to detect the critical micelle concentration (CMC) and thus its surface and thermodynamic parameters were calculated. Solubilization of this drug within micelles of anionic surfactant sodium dodecyl sulfate (SDS) has also been studied. UV/Visible spectroscopy was used to calculate partition coefficient (Kx), free energy of partition and number of drug molecules per micelle. The complexation of drug with HSA at physiological conditions (pH 7.4) has also been analyzed by using UV/Visible and fluorescence spectroscopy. The values of drug-protein binding constant, number of binding sites and free energy of binding were calculated

  10. Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone-Chloroquine Hybrids.

    Science.gov (United States)

    Andayi, Warren A; Egan, Timothy J; Gut, Jiri; Rosenthal, Philip J; Chibale, Kelly

    2013-07-11

    A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM). PMID:24900724

  11. The efficacy of chloroquine treatment against naturally occuring Giardia duodenalis infection in lambs

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    Umit Karademir

    2016-05-01

    Full Text Available Objective. The aim of the present study was to determine the efficacy of Chloroquine (Cq, an antimalarial medicine, administered at a dose of 2.5 mg/kg, orally, during 5 consecutive days, in Sakiz and Merino lambs naturally infected with Giardia duodenalis. Materials and methods. To this extent weaned 10 weeks of aged lambs were enrolled and randomly assigned into two groups based on treatment (group C, n=18 lambs treated with Cq and placebo (group P, n=8 untreated control animals. Diagnosis was based on detection of trophozoit and/or cysts on fecal flotation. Cyst count per gram feces (days 0, 3, 7 and 10 was analyzed among groups. Results. During the trial, regarding the efficacy of Cq on days 3., 7., and 10. There was significant (p<0.01 reduction in cyst excretion; whereas evaluation of mean geometric cyst excretion revealed 100% reduction. Conclusions. There was a very high (100% reduction in cyst excretion in the Cq treatment group compared to the positive untreated control group on days 3, 7 and 10, resulting in a significant (p<0.001 reduction, making Cq, safety, and thus highly effective treatment option of lambs with naturally occuring giardiasis.

  12. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    Science.gov (United States)

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  13. Chitosan/Sterculia striata polysaccharides nanocomplex as a potential chloroquine drug release device.

    Science.gov (United States)

    Magalhães, Guilherme A; Moura Neto, Erico; Sombra, Venícios G; Richter, Ana R; Abreu, Clara M W S; Feitosa, Judith P A; Paula, Haroldo C B; Goycoolea, Francisco M; de Paula, Regina C M

    2016-07-01

    Nanoparticles are produced by means of polyelectrolyte complexation (PEC) of oppositely charged polycationic chitosan (CH) with polyanionic polysaccharide extracted from Sterculia striata exudates (rhamnogalacturonoglycan (RG)-type polysaccharide). The nanoparticles formed with low-molar-mass CH are larger than those formed with high-molar-mass CH. This behavior is in contrast with that previously observed for other systems and may be attributed to different mechanisms related to the association of CH with RG of higher persistence length chain than that of CH. Nanoparticles harnessed with a charge ratio (n(+)/n(-)) of <1 are smaller than particles with an excess of polycations. Particles with hydrodynamic sizes smaller than 100nm are achieved using a polyelectrolyte concentration of 10(-4)gmL(-1) and charge ratio (n(+)/n(-)) of <1. The CH/RG nanoparticles are associated with chloroquine (CQ) with an efficiency of 28% and release it for up to ∼60% within ∼10h, whereas in the latter, only ∼40% of the CQ was released after 24h. The main factor that influenced drug release rate is the nanoparticle charge ratio.

  14. Signaling of chloroquine-induced stress in the yeast Saccharomyces cerevisiae requires the Hog1 and Slt2 mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Baranwal, Shivani; Azad, Gajendra Kumar; Singh, Vikash; Tomar, Raghuvir S

    2014-09-01

    Chloroquine (CQ) has been under clinical use for several decades, and yet little is known about CQ sensing and signaling mechanisms or about their impact on various biological pathways. We employed the budding yeast Saccharomyces cerevisiae as a model organism to study the pathways targeted by CQ. Our screening with yeast mutants revealed that it targets histone proteins and histone deacetylases (HDACs). Here, we also describe the novel role of mitogen-activated protein kinases Hog1 and Slt2, which aid in survival in the presence of CQ. Cells deficient in Hog1 or Slt2 are found to be CQ hypersensitive, and both proteins were phosphorylated in response to CQ exposure. CQ-activated Hog1p is translocated to the nucleus and facilitates the expression of GPD1 (glycerol-3-phosphate dehydrogenase), which is required for the synthesis of glycerol (one of the major osmolytes). Moreover, cells treated with CQ exhibited an increase in intracellular reactive oxygen species (ROS) levels and the effects were rescued by addition of reduced glutathione to the medium. The deletion of SOD1, the superoxide dismutase in yeast, resulted in hypersensitivity to CQ. We have also observed P38 as well as P42/44 phosphorylation in HEK293T human cells upon exposure to CQ, indicating that the kinds of responses generated in yeast and human cells are similar. In summary, our findings define the multiple biological pathways targeted by CQ that might be useful for understanding the toxicity modulated by this pharmacologically important molecule.

  15. Powder properties of binary mixtures of chloroquine phosphate with lactose and dicalcium phosphate

    Directory of Open Access Journals (Sweden)

    Michael Ayodele Odeniyi

    2010-09-01

    Full Text Available A study was conducted on the packing and cohesive properties of chloroquine phosphate in binary mixtures with lactose and dicalcium phosphate powders. The maximum volume reduction due to packing as expressed by the Kawakita constant, a, and the angle of internal flow, θ, were the assessment parameters. The individual powders were characterized for their particle size and shape using an optical microscope. Binary mixtures of various proportions of chloroquine phosphate with lactose and dicalcium phosphate powders were prepared. The bulk and tapped densities, angles of repose and internal flow, as well as compressibility index of the materials were determined using appropriate parameters. The calculated and determined values of maximum volume reduction for the binary mixtures were found to differ significantly (PRealizou-se estudo das propriedades de empacotamento e de coesão do fosfato de cloroquina em misturas binárias com lactose e fosfato dicálcico em pó. O volume máximo de redução devido ao empacotamento, segundo expresso pela constante de Kawakita, a, e o ângulo de fluxo interno, θ, foram os parâmetros de avaliação. Os pós individuais foram caracterizados por seu tamanho e forma de partículas, utilizando microscópio óptico. Prepararam-se misturas binárias de várias proporções de fosfato de cloroquine e lactose e fosfato dicálcico em pó. As densidades de bulk and tapped, os ângulos de repouso e de fluxo interno e o índice de compressibilidade dos materiais foram determinados utilizando-se parâmetros apropriados. Os valores calculados e determinados do volume máximo de redução para as misturas binárias mostraram-se significativamente diferentes (P< 0,05, sendo o traçado de Kawakita mais confiável na determinação das propriedades de empacotamento. O tipo de diluente influenciou as propriedades de fluxo das misturas com fosfato dicálcico, dando resultados previsíveis, enquanto as misturas contendo lactose

  16. FORMULATION AND EVALUATION OF TASTE MASKED DISPERSIBLE TABLETS OF CHLOROQUINE PHOSPHATE

    Directory of Open Access Journals (Sweden)

    Moon Rajkumar Sukdeo

    2012-09-01

    Full Text Available The primary aim of present work was to formulate and evaluate taste masked dispersible tablets of Chloroquine phosphate, an antimalarial drug, using ion exchange resins like INDION 294 and TULSION 339 as a taste masking agent and superdisintegrating agents like crospovidone and sodium starch glycolate in different concentrations. Characterization of drug was done by melting point determination, FT-IR spectroscopy and UV-spectroscopy. Drug-resin complexes were prepared by batch method using the resins in different ratios. Drug loading study was carried at different pH. INDION 294 showed highest drug loading (93.31%. Hence, further studies were done using INDION 294. The drug-resin complexes were studied for micromeritic properties, in vitro drug release and taste masking ability by determining threshold bitterness concentration of the drug. The complexes were characterized by drug content, FTIR and DSC studies. Powder blends were prepared and evaluated for various physical properties. Dispersible tablets of drug-resin complex (DRC were prepared by wet granulation method using crospovidone and sodium starch glycolate in different concentrations as superdisintegrants. Tablets were evaluated for thickness, hardness, friability, uniformity of weight, dispersion time, uniformity of dispersion, disintegration time, wetting time, wetting volume, content of active ingredient and dissolution studies. All the formulations showed the evaluated parameters within the acceptable limits for dispersible tablets. Finally, formulation F3 was taken as an optimized formulation which was containing 3% of crospovidone and showed the least in vitro disintegration time and an excellent drug release. Stability study was also conducted on the optimized batch F3 which showed good results.

  17. Chloroquine and its derivatives exacerbate B19V-associated anemia by promoting viral replication.

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    Claudia Bönsch

    Full Text Available BACKGROUND: An unexpectedly high seroprevalence and pathogenic potential of human parvovirus B19 (B19V have been observed in certain malaria-endemic countries in parallel with local use of chloroquine (CQ as first-line treatment for malaria. The aims of this study were to assess the effect of CQ and other common antimalarial drugs on B19V infection in vitro and the possible epidemiological consequences for children from Papua New Guinea (PNG. METHODOLOGY/PRINCIPAL FINDINGS: Viral RNA, DNA and proteins were analyzed in different cell types following infection with B19V in the presence of a range of antimalarial drugs. Relationships between B19V infection status, prior 4-aminoquinoline use and anemia were assessed in 200 PNG children <10 years of age participating in a case-control study of severe infections. In CQ-treated cells, the synthesis of viral RNA, DNA and proteins was significantly higher and occurred earlier than in control cells. CQ facilitates B19V infection by minimizing intracellular degradation of incoming particles. Only amodiaquine amongst other antimalarial drugs had a similar effect. B19V IgM seropositivity was more frequent in 111 children with severe anemia (hemoglobin <50 g/L than in 89 healthy controls (15.3% vs 3.4%; P = 0.008. In children who were either B19V IgM or PCR positive, 4-aminoquinoline use was associated with a significantly lower admission hemoglobin concentration. CONCLUSIONS/SIGNIFICANCE: Our data strongly suggest that 4-aminoquinoline drugs and their metabolites exacerbate B19V-associated anemia by promoting B19V replication. Consideration should be given for choosing a non-4-aminoquinoline drug to partner artemisinin compounds in combination antimalarial therapy.

  18. Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen.

    Science.gov (United States)

    Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L

    2015-09-01

    Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium ‎falciparum‎. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax.

  19. In vitro effect of chloroquine, mefloquine and quinine on human lymphocyte proliferative responses to malaria antigens and other antigens/mitogens

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Theander, T G; Andersen, B J;

    1986-01-01

    The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C-thymidine incorp......The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C......-thymidine incorporation. On a weight base, the most potent drug was mefloquine. At clinically relevant doses, chloroquine and mefloquine did not affect the response to malaria antigens, but mefloquine decreased the response to phytohaemagglutinin; quinine suppressed the response to all mitogens (with the exception...

  20. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars;

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  1. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.

    Science.gov (United States)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars; Rodrigues, Amabelia; Ursing, Johan

    2015-02-01

    In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) childrenquinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

  2. Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau

    DEFF Research Database (Denmark)

    Kofoed, Poul-Erik; Ursing, Johan; Poulsen, Anja;

    2007-01-01

    The aim of the present study was to compare different doses of chloroquine (CQ) and amodiaquine (AQ) for the treatment of falciparum malaria in children. Children with Plasmodium falciparum monoinfection were allocated by block randomisation to treatment with CQ 50/kg mg or 25 mg/kg or AQ 15 mg...... is not superior to treatment with CQ 50 mg/kg. However, 25 mg/kg of CQ is less efficient. As an interim option, Guinea-Bissau could change the recommended first-line treatment of uncomplicated malaria to CQ 50 mg/kg, reserving AQ as a partner drug for a future combination therapy....

  3. The effects of chloroquine and hydroxychloroquine on nitric oxide production in RAW 264.7 and bone marrow-derived macrophages.

    Science.gov (United States)

    Perečko, T; Kassab, R B; Vašíček, O; Pekarová, M; Jančinová, V; Lojek, A

    2014-01-01

    Chloroquine, an antimalarial drug, can also be used in the regulation of the immune system, e.g. it is used in the treatment of autoimmune diseases. In this study we investigated the effects of chloroquine and its hydroxy-derivative on nitric oxide (NO) production in two different cell types: (i) immortalized mouse macrophage cell line RAW 264.7 and (ii) mouse bone marrow-derived macrophages (BMDM). The cells were treated with different concentrations (1-100 μM) of chloroquine or hydroxychloroquine and stimulated with lipopolysaccharide for 24 h to induce NO production. Measurement of nitrites by the Griess reaction was used to evaluate the production of NO. Expression of inducible NO synthase was evaluated with Western blot and ATPcytotoxicity test was used to measure the viability of the cells. Our results showed that both chloroquine and its hydroxy-derivative inhibited NO production in both cell types. However, based on the results of LD50 these inhibitory effects of both derivatives were due to their cytotoxicity. The LD50 values for chloroquine were 24.77 μM (RAW 264.7) and 24.86 μM (BMDM), the LD50 for hydroxychloroquine were 13.28 μM (RAW 264.7) and 13.98 μM (BMDM). In conclusion, hydroxychloroquine was more cytotoxic than its parent molecule. Comparing the two cell types tested, our data suggest that there are no differences in cytotoxicity of chloroquine or hydroxychloroquine for primary cells (BMDM) or immortalized cell line (RAW 264.7). PMID:25369339

  4. Antiplasmodial activity-aided isolation and identification of quercetin-4'-methyl ether in Chromolaena odorata leaf fraction with high activity against chloroquine-resistant Plasmodium falciparum.

    Science.gov (United States)

    Ezenyi, I C; Salawu, O A; Kulkarni, R; Emeje, M

    2014-12-01

    The present study was undertaken to evaluate the antiplasmodial activity of Chromolaena odorata leaf extract and gradient fractions through in vivo and in vitro tests, aimed at identifying its antiplasmodial constituents. Sub-fractions obtained from the most active gradient fraction were further tested for cytotoxicity against THP-1 cells, chloroquine-sensitive (HB3) and chloroquine-resistant (FCM29) Plasmodium falciparum. Our results showed the dichloromethane gradient fraction was most effective, significantly (P odorata leaves, which exhibit potential for development as medicine against malaria. PMID:25199554

  5. Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010

    Directory of Open Access Journals (Sweden)

    Rungsihirunrat Kanchana

    2011-02-01

    Full Text Available Abstract Background In Thailand, the proportion of Plasmodium vivax infection has become equal to Plasmodium falciparum. Reports of a trend of gradual decline of in vitro sensitivity of P. vivax to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance P. vivax in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with in vitro sensitivity of P. vivax isolates. Methods The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008 - August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females with mono-infection of P. vivax malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days and the anti-relapse drug primaquine (15 mg for 14 days. In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition assay. Results All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred during the investigation period. In vitro data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI values of IC50 for chloroquine were 100.1 and 134.7 (1.1-264.9 nM, respectively. Conclusion In vivo results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with P. vivax in the Thai-Myanmar border area. In vitro sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of P. vivax is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to

  6. Failure of Supervised Chloroquine and Primaquine Regimen for the Treatment of Plasmodium vivax in the Peruvian Amazon

    Directory of Open Access Journals (Sweden)

    Paul C. F. Graf

    2012-01-01

    Full Text Available The widespread use of primaquine (PQ and chloroquine (CQ, together, may be responsible for the relatively few, isolated cases of chloroquine-resistant P. vivax (CQRPV that have been reported from South America. We report here a case of P. vivax from the Amazon Basin of Peru that recurred against normally therapeutic blood levels of CQ. Four out of 540 patients treated with combination CQ and PQ had a symptomatic recurrence of P. vivax parasitemia within 35 days of treatment initiation, possibly indicating CQ failure. Whole blood total CQ level for one of these four subjects was 95 ng/ml on the day of recurrence. Based on published criteria that delineate CQRPV as a P. vivax parasitemia, either recrudescence or relapse, that appears against CQ blood levels >100 ng/mL, we document the occurrence of a P. vivax strain in Peru that had unusually high tolerance to the synergistic combination therapy of CQ + PQ that normally works quite well.

  7. Influence of ginger and banana starches on the mechanical and disintegration properties of chloroquine phosphate tab-lets

    Institute of Scientific and Technical Information of China (English)

    O.A.Odeku; M.A.Odeniyi; G.O.Ogunlowo

    2009-01-01

    Objective:The influence of two experimental starches -ginger starch obtained from Zingiber officinale and ba-nana starch from Musa sapientum -on the mechanical and disintegration properties of chloroquine tablets have been studied in comparison with the influence of official corn starch.Methods:Chloroquine tablets were for-mulated using various concentarions of the starches as binding agent.The mechanical properties of the tablets were assessed in terms of crushing strength and friability and the crushing strength-friability ratio (CSFR) while drug release properties were evaluated based on disintegration and the time of tablets.Results:The ranking for crushing strength and CSFR was corn >banana >ginger starch while the ranking was reverse for friability.The disintegration time increased with packing fraction and starch concentration in the rank order of formulations containing corn >banana >ginger starch.The CSFR/DT values increased with concentration of starch binder indicating an improved balance between binding and disintegrant properties of the starches.Sta-tistical analysis showed that there were significant (P <0.001)difference in the CSFR/DT for tablets contai-ning the various starch binders.Conclusion:The mechanical and disintegration properties of the experimental starches compared favorably with those of corn starch and ginger starch could be more useful when faster tablet disintegration is desired.

  8. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    Science.gov (United States)

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated. PMID:25783783

  9. Characterization and evaluation of acid-modified starch of Dioscorea oppositifolia (Chinese yam as a binder in chloroquine phosphate tablets

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    Adenike Okunlola

    2013-12-01

    Full Text Available Chinese yam (Dioscorea oppositifolia starch modified by acid hydrolysis was characterized and compared with native starch as a binder in chloroquine phosphate tablet formulations. The physicochemical and compressional properties (using density measurements and the Heckel and Kawakita equations of modified Chinese yam starch were determined, and its quantitative effects as a binder on the mechanical and release properties of chloroquine phosphate were analyzed using a 2³ full factorial design. The nature (X1, concentration of starch (X2 and packing fraction (X3 were taken as independent variables and the crushing strength-friability ratio (CSFR, disintegration time (DT and dissolution time (t80 as dependent variables. Acid-modified Chinese yam starch showed a marked reduction (p<0.05 in amylose content and viscosity but increased swelling and water-binding properties. The modified starch had a faster onset and greater amount of plastic flow. Changing the binder from native to acid-modified form led to significant increases (p<0.05 in CSFR and DT but a decrease in t80. An increase in binder concentration and packing fraction gave similar results for CSFR and DT only. These results suggest that acid-modified Chinese yam starches may be useful as tablet binders when high bond strength and fast dissolution are required.

  10. Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT).

    Science.gov (United States)

    Callaghan, Paul S; Hassett, Matthew R; Roepe, Paul D

    2015-08-18

    At least 53 distinct isoforms of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein are expressed in strains or isolates of P. falciparum malarial parasites from around the globe. These parasites exhibit a range of sensitivities to chloroquine (CQ) and other drugs. Mutant PfCRT is believed to confer cytostatic CQ resistance (CQR(CS)) by transporting CQ away from its DV target (free heme released upon hemoglobin digestion). One theory is that variable CQ transport catalyzed by these different PfCRT isoforms is responsible for the range of CQ sensitivities now found for P. falciparum. Alternatively, additional mutations in drug-selected parasites, or additional functions of PfCRT, might complement PfCRT-mediated CQ transport in conferring the range of observed resistance phenotypes. To distinguish between these possibilities, we recently optimized a convenient method for measuring PfCRT-mediated CQ transport, involving heterologous expression in Saccharomyces cerevisiae. Here, we use this method to quantify drug transport activity for 45 of 53 of the naturally occurring PfCRT isoforms. Data show that variable levels of CQR likely depend upon either additional PfCRT functions or additional genetic events, including perhaps changes that influence DV membrane potential. The data also suggest that the common K76T PfCRT mutation that is often used to distinguish a P. falciparum CQR phenotype is not, in and of itself, a fully reliable indicator of CQR status.

  11. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    Science.gov (United States)

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated.

  12. Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

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    Takahashi Nobuyuki

    2012-03-01

    Full Text Available Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ is conferred by a K to T mutation at amino acid position 76 (K76T in the P. falciparum CQ transporter (PfCRT. To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand, Melanesia (Papua New Guinea and Vanuatu and Africa (Ghana. A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76, four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined. Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95 and CVIDT (n = 14, indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71 and CVMNT (n = 3. In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance

  13. Are Long-Term Chloroquine or Hydroxychloroquine Users Being Checked Regularly for Toxic Maculopathy?

    Science.gov (United States)

    Nika, Melisa; Blachley, Taylor S.; Edwards, Paul; Lee, Paul P.; Stein, Joshua D.

    2014-01-01

    Importance According to evidence-based, expert recommendations, long-term users of chloroquine (CQ) or hydroxychloroquine (HCQ) should undergo regular visits to eye-care providers and diagnostic testing to check for maculopathy. Objective To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking CQ or HCQ are regularly visiting eye-care providers and being screened for maculopathy. Setting, Design and Participants Patients with RA or SLE who were continuously enrolled in a particular managed-care network for ≥5 years during 2001-2011 were studied. Patients' amount of CQ/HCQ use in the 5 years since initial RA/SLE diagnosis was calculated, along with their number of eye-care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Visits to eye providers and diagnostic testing for maculopathy were assessed for each enrollee over the study period. Logistic regression was performed to assess potential factors associated with regular eye-care-provider visits (≥3 in 5 years) among CQ/HCQ users, including those at greatest risk for maculopathy. Main Outcome Measures Among CQ/HCQ users and those at high risk for toxic maculopathy, the proportions with regular eye-care visits and diagnostic testing, and the likelihood of regular eye-care visits (odds ratios [ORs] with 95% confidence intervals [CI]). Results Among 18,051 beneficiaries with RA or SLE, 6,339 (35.1%) had ≥1 record of HCQ/CQ use and 1,409 (7.8%) used HCQ/CQ for ≥4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye-provider visits, 6.1% had no visits to eye providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of HCQ/CQ use was associated with a 2.0%-increased likelihood of regular eye care (adjusted OR=1.02, CI=1.01-1.03). High-risk patients whose SLE/RA were managed by rheumatologists had a 77%-increased

  14. From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia

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    Snow Robert W

    2008-01-01

    Full Text Available Abstract Background Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT. Methods All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy. Results A decision was made to change national drug policy to artemether-lumefantrine (AL in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004. Conclusion Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires

  15. Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Dalgaard, Michael B; Lusingu, John P;

    2006-01-01

    Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We i...

  16. Chloroquine improved carbon tetrachloride-induced liver fibrosis through its inhibition of the activation of hepatic stellate cells: role of autophagy.

    Science.gov (United States)

    He, Wei; Wang, Bin; Yang, Jing; Zhuang, Yun; Wang, Liangzhi; Huang, Xiaodan; Chen, Jianping

    2014-01-01

    Autophagy is involved in the activation of hepatic stellate cells (HSCs), which is the key process of liver fibrosis. We reasoned that chloroquine, based on its ability to inhibit autophagy, might exert beneficial effects in liver fibrosis. Liver fibrosis in rats was induced by carbon tetrachloride (CCl4). Rats were divided into three groups, a normal control group (N group), model group (M group), and chloroquine group (CQ group). Liver fibrosis in the rats was evaluated by hematoxyline-eosin (H&E) and Masson staining. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) were determined using an automated biochemistry analyzer. Total hepatic hydroxyproline levels were determined with a kit. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were detected by immunofluorescence staining, and the expressions of LC3-II and p62 were determined by Western blotting. Compared with N group, M group showed impaired liver function, liver fibrosis, increased hydroxyproline content, up-regulated expressions of α-SMA and TGF-β1, which have been reported to be pro-fibrogenic genes in vivo, and increased autophagy flux as indicated by the accumulation of LC3-II and degradation of p62. These changes were attenuated by chloroquine treatment. Chloroquine exerts beneficial effects in CCl4-induced liver fibrosis. The mechanism of action includes inhibition of autophagy pathways and inhibition of activation of HSCs. PMID:25177034

  17. A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

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    Ngoma Ghyslain

    2011-10-01

    Full Text Available Abstract Background Chloroquine resistance (CR decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR conferring mutant pfcrt allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ to artesunate plus amodiaquine (AQ in 2003. Methods The prevalence of the wild type pfcrt allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the pfcrt locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates, 2002 (47 isolates and 2005 - 07 (55 isolates. Results The prevalence of the mutant pfcrt allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the pfcrt locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. Pfcrt haplotype analysis showed that all wild type alleles were CVMNK. Conclusion Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant pfcrt allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant pfcrt haplotype even after discontinuance of CQ usage.

  18. Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine

    Science.gov (United States)

    Bell, Andrew M; Gutierrez-Mecinas, Maria; Polgár, Erika; Todd, Andrew J

    2016-01-01

    Background Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Results Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP–EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP–EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Conclusions Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway. PMID:27270268

  19. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    DEFF Research Database (Denmark)

    Khalil, Insaf F; Alifrangis, Michael; Recke, Camilla;

    2011-01-01

    therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite......In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma....

  20. Molecular analysis of chloroquine and sulfadoxine-pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua.

    Science.gov (United States)

    Sridaran, Sankar; Rodriguez, Betzabe; Soto, Aida Mercedes; Macedo De Oliveira, Alexandre; Udhayakumar, Venkatachalam

    2014-05-01

    Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.

  1. Effects of chloroquine and sulfadoxine/pyrimethamine on gametocytes in patients with uncomplicated Plasmodium falciparum malaria in Colombia

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    Lyda Osorio

    2002-12-01

    Full Text Available The effect of antimalarials on gametocytes can influence transmission and the spread of drug resistance. In order to further understand this relationship, we determined the proportion of gametocyte carriers over time post-treatment in patients with uncomplicated Plasmodium falciparum malaria who were treated with either chloroquine (CQ or sulfadoxine/pyrimethamine (SP. The overall proportion of gametocyte carriers was high (85% and not statistically significantly different between the CQ and SP treatment groups. However, an increased risk of carrying gametocytes on day 14 of follow up (1.26 95% CI 1.10-1.45 was found among patients having therapeutic failure to CQ compared with patients having an adequate therapeutic response. This finding confirms and extends reports of increased risk of gametocytaemia among CQ resistant P. falciparum.

  2. FET-PET-based reirradiation and chloroquine in patients with recurrent glioblastoma. First tolerability and feasibility results

    Energy Technology Data Exchange (ETDEWEB)

    Bilger, Angelika; Bittner, Martin-Immanuel; Grosu, Anca L.; Wiedenmann, Nicole; Firat, Elke; Niedermann, Gabriele; Milanovic, Dusan [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); Meyer, Philipp T. [University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Weber, Wolfgang A. [University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Memorial Sloan-Kettering Cancer Center, Molecular Imaging and Therapy Service, York Avenue, NY (United States)

    2014-10-15

    Treatment of recurrent glioblastoma (rGBM) remains an unsolved clinical problem. Reirradiation (re-RT) can be used to treat some patients with rGBM, but as a monotherapy it has only limited efficacy. Chloroquine (CQ) is an anti-malaria and immunomodulatory drug that may inhibit autophagy and increase the radiosensitivity of GBM. Between January 2012 and August 2013, we treated five patients with histologically confirmed rGBM with re-RT and 250 mg CQ daily. Treatment was very well tolerated; no CQ-related toxicity was observed. At the first follow-up 2 months after finishing re-RT, two patients achieved partial response (PR), one patient stable disease (SD), and one patient progressive disease (PD). One patient with reirradiated surgical cavity did not show any sign of PD. In this case series, we observed encouraging responses to CQ and re-RT. We plan to conduct a CQ dose escalation study combined with re-RT. (orig.) [German] Die Behandlung rezidivierter Glioblastome (rGBM) ist problematisch. Manche Patienten koennen erneut bestrahlt (re-RT) werden, jedoch nur mit begrenzter Wirksamkeit. Das Antimalariamittel Chloroquin (CQ) wirkt immunmodulatorisch, hemmt die Autophagie und kann die Radiosensibilitaet erhoehen. Zwischen Januar 2012 und August 2013 wurden 5 Patienten mit einem histologisch gesicherten rGBM mit re-RT und zusaetzlich taeglich 250 mg CQ behandelt. Diese Behandlung wurde sehr gut, ohne CQ-assoziierte Nebenwirkungen toleriert. Zum ersten Follow-up, 2 Monate nach der re-RT, fanden sich zwei partielle Remissionen (PR), ein stabiler Verlauf (SD) und ein Progress (PD). Ein zuvor operierter Patient war in anhaltender Remission. Diese Fallstudie zeigt ein ermutigendes Ansprechen von Patienten mit rGBM auf eine Behandlung mit CQ und re-RT. Eine Dosiseskalationsstudie CQ/re-RT ist geplant. (orig.)

  3. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    Science.gov (United States)

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J; Volkman, Sarah K; Wirth, Dyann F; Legrand, Eric; Fidock, David A; Neafsey, Daniel E; Musset, Lise

    2015-09-15

    In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.

  4. The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

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    Atroosh Wahib M

    2012-08-01

    Full Text Available Abstract Background Malaria is still a public health problem in Malaysia with chloroquine (CQ being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr1 at codons 86 and 1246, as molecular markers of CQ resistance. Methods A total of 75 P. falciparum blood samples were collected from different districts of Pahang state, Malaysia. Single nucleotide polymorphisms in pfcrt gene (codons 76, 271, 326, 356 and 371 and pfmdr1 gene (codons 86 and 1246 were analysed by using mutation-specific nested PCR and restriction fragment length polymorphism (PCR-RFLP methods. Results Mutations of pfcrt K76T and pfcrt R371I were the most prevalent among pfcrt gene mutations reported by this study; 52% and 77%, respectively. Other codons of the pfcrt gene and the positions 86 and 1246 of the pfmdr1 gene were found mostly of wild type. Significant associations of pfcrt K76T, pfcrt N326S and pfcrt I356T mutations with parasitaemia were also reported. Conclusion The high existence of mutant pfcrt T76 may indicate the low susceptibility of P. falciparum isolates to CQ in Peninsular Malaysia. The findings of this study establish baseline data on the molecular markers of P. falciparum CQ resistance, which may help in the surveillance of drug resistance in Peninsular Malaysia.

  5. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

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    Mwapasa Victor

    2009-03-01

    Full Text Available Abstract Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (P. falciparum isolates on the island. Previously, minority variant chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA, which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7% of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the surveillance of anti-malarial resistance. The use of a non-radioactive label allows for the use of HTAs in malaria endemic countries.

  6. [Mutant alleles associated to chloroquine and sulfadoxine-pyrimethanime resistance in Plasmodium falciparum of the Ecuador-Peru and Ecuador-Colombia borders].

    Science.gov (United States)

    Arróspide, Nancy; Hijar-Guerra, Gisely; de Mora, Doménica; Diaz-Cortéz, César Eduardo; Veloz-Perez, Raúl; Gutierrez, Sonia; Cabezas-Sánchez, César

    2014-04-01

    The frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.

  7. The effect of prophylaxis with chloroquine and proguanil on delayed-type hypersensitivity and antibody production following vaccination with diphtheria, tetanus, polio, and pneumococcal vaccines

    DEFF Research Database (Denmark)

    Gyhrs, A; Pedersen, B K; Bygbjerg, I;

    1991-01-01

    (1,000 mg/week), or 4) proguanil hydrochloride (200 mg/day) for six weeks. Skin testing was performed on days 0 and 28. Vaccinations with diphtheria, tetanus, polio, and pneumococcal polysaccharide antigen vaccines were performed on day 28, and the presence of specific antibodies was determined...... dosages, does not induce any detectable suppression of delayed-type hypersensitivity or vaccination responses to diphtheria, tetanus, polio, or pneumococcal polysaccharide antigens....... with seven delayed-type common antigens (Multitest) and 2) humoral immunity by measurement of specific antibody response to vaccination. Sixty healthy young individuals were randomized into four groups and given 1) no treatment (controls), 2) chloroquine diphosphate (500 mg/week), 3) chloroquine diphosphate...

  8. Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum

    Science.gov (United States)

    BARLIANA, MELISA I.; SURADJI, EKA W.; ABDULAH, RIZKY; DIANTINI, AJENG; HATABU, TOSHIMITSU; NAKAJIMA-SHIMADA, JUNKO; SUBARNAS, ANAS; KOYAMA, HIROSHI

    2014-01-01

    Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported to have several biological activities. The ethanol extract of S. wallichii was fractionated based on polarity using n-hexane, ethyl acetate and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant Plasmodium falciparum (P. falciparum) at 100 μg/ml for 72 h. The major compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. The characterized compound was also tested against chloroquine-resistant P. falciparum in culture to evaluate its antiplasmodial activity. The ethanol extract of S. wallichii at 100 μg/ml exhibited a significant parasite shrinkage after 24 h of treatment. The ethyl acetate fraction at 100 μg/ml was the most active fraction against chloroquine-resistant P. falciparum. Based on the structural characterization, the major compound isolated from the ethyl acetate fraction was kaempferol-3-O-rhamnoside, which showed promising antiplasmodial activity against chloroquine-resistant P. falciparum with an IC50 of 106 μM after 24 h of treatment. The present study has provided a basis for the further investigation of kaempferol-3-O-rhamnoside as an active compound for potential antimalarial therapeutics. PMID:24944812

  9. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

    OpenAIRE

    Walter-Sack Ingeborg; Tapsoba Théophile; Sanon Mamadou; Jahn Albrecht; Schiek Wolfgang; Rengelshausen Jens; Mansmann Ulrich; Coulibaly Boubacar; Witte Steffen; Mandi Germain; Meissner Peter E; Mikus Gerd; Burhenne Jürgen; Riedel Klaus-Dieter; Schirmer Heiner

    2005-01-01

    Abstract Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a r...

  10. Multiple Origins of Mutations in the mdr1 Gene--A Putative Marker of Chloroquine Resistance in P. vivax.

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    Mette L Schousboe

    2015-11-01

    Full Text Available Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR. Single nucleotide polymorphisms (SNPs in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored.In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS loci flanking the Pvmdr1 gene.We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, São Tomé and Ecuador. We measured and diversity in four microsatellite (MS markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles.SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5, 13.3% (n = 28 of the samples were single mutant MYF, 63.0% of samples (n = 133 were double mutant MYL, and 21.3% (n = 45 were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He, was seen in the complete sample set (He = 0.99, while He estimates for individual loci ranged from 0.00-0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic

  11. Antiplasmodial activity of certain medicinal plants against chloroquine resistant Plasmodium berghei infected white albino BALB/c mice.

    Science.gov (United States)

    Rajendran, C; Begam, M; Kumar, Dharmendra; Baruah, Indra; Gogoi, H K; Srivastava, R B; Veer, Vijay

    2014-06-01

    In the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of Psidium guajava, leaves of Ocimum sanctum and leaves of Murraya koenigii are evaluated against Plasmodium berghei (chloroquine resistant NK65 strain) infected white albino BALB/c mice. A 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (Group I) and drug control with Chloroquine, 50 mg/kg body weight (Group II). All the parts were extracted based on the decoction method, which is commonly seen among the villagers/tribes as their usual method of preparation of decoction for most of the ailments. The antimalarial activities were evaluated from the giemsa stained blood smears collected from different treated groups of mice used in this experiment. The antiplasmodial effect that is percent parasitaemia and percent suppression (values in parenthesis) showed by the treated groups of mice at 350 mg/kg b. wt. by the aqueous extracts of P. guajava leaves (Group III) was 19.8 ± 1.22 (73.7 %), P. guajava unripe fruits (Group IV) was 52.7 ± 2.19 (30.0 %), leaves of O. sanctum (Group V) was 64.0 ± 0.73 (15.1 %) and leaves of M. koenigii (Group VI) was 28.9 ± 0.81 (61.6 %) whereas at 750 mg/kg b. wt., it all showed 10.3 ± 0.7 (80.2 %), 26.3 ± 0.52 (65.1 %), 42.0 ± 0.47 (44.2 %) and 14.9 ± 0.46 (71.5 %) whereas at 1,000 mg/kg b. wt. dose, it all showed 9.2 ± 0.39 (85.8 %), 25.6 ± 0.40 (62.0 %), 41.8 ± 0.29 (35.5 %) and 14.0 ± 0.42 (76.9 %) respectively. PMID:24808642

  12. Microsatellite polymorphism within pfcrt provides evidence of continuing evolution of chloroquine-resistant alleles in Papua New Guinea

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    Sharma Yagya D

    2007-03-01

    Full Text Available Abstract Background Polymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR, as sensitive strains consistently carry lysine (K, while CQR strains carry threonine (T at the codon 76. Previous studies have shown that microsatellite (MS haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG. Methods Here, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively, locus-by-locus and haplotype heterozygosity (H analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles. Results For MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb to 0.094 (9B12, +2 kb suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901 in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site. Conclusion In this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T and its immediate flanking region indicate homogenisation in PNG CQR parasite populations

  13. How sulfadoxine-pyrimethamine (SP was perceived in some rural communities after phasing out chloroquine (CQ as a first-line drug for uncomplicated malaria in Tanzania: lessons to learn towards moving from monotherapy to fixed combination therapy

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    Nsimba Stephen ED

    2006-01-01

    Full Text Available Abstract Malaria is a leading cause of death in Sub-Saharan Africa. Tanzania changed its malaria treatment policy from chloroquine (CQ to Sulphadoxine-Pyrimethamine (SP as first line drug in August 2001. We wanted to assess the perception and behaviour about SP after phasing out chloroquine which was very popular, cheap, available, and was preferred by many people for self-medication in homes as it was considered to have minimal side effects. Focus Group Discussions (FGDs were carried out after one year of the anti-malarial drug treatment policy change in the country. The FGD themes were on malaria for under-five children and other age groups, anti-malarial drug use through self-medications, specific experiences people had about SP drug for both mothers/guardians, men in the communities and health workers. A total of twelve FGDs were performed with mothers/guardians, men and health workers in the selected public health care facilities in the district. In the FGDs people feared adverse reactions from SP; its slow ability of reducing fever and self-treatment in this case was less reported from the mothers/guardians groups. However, SP was reported by health workers to be administered using the direct observation approach under supervision in their health care facilities. This was done in order to increase compliance as there were worries that some mothers were throwing away the drug if they were instructed by health workers to go and administer SP to their sick children at home. Based on this information, it is obvious that fear and negative perceptions about SP drug was common in the study setting. As evidence of this, there was less reported home-stocking and self-medication in the discussions for this particular recommended new first-line anti-malarial. The public has demonstrated a lack of confidence in SP. Furthermore, some health workers expressed obvious fear and negative perceptions towards the drug despite the fact that some FGDs with

  14. Assessment of compliance to sulfadoxine-pyrimethamine 18 months after phasing out chloroquine in Mkuranga District, Coast region-Tanzania

    Institute of Scientific and Technical Information of China (English)

    Stephen ED Nsimba; Phare G Mujinja

    2010-01-01

    Objective:To observe and assess the compliance to sulfadoxine-pyrimethamine (SP) one and a half years after phasing out chloroquine (CQ) in Mkuranga District, Coast region, Tanzania. Methods:A randomly controlled baseline community study was conducted in rural areas of Mkuranga district, Tanzania. Semi-structured questionnaire consisted of open-and closed-ended questions including home stocking, home use, last fever episodes and treatment of underfives with malaria using CQ or SP. Results:The prevalence of fever or reported fever rate during the last 48 hours by their mothers or guardians was high (70%). Of all 117 blood samples, only 8 children after drug analysis were found to have CQ and 13 had SP concentrations within their blood respectively. None of these blood drug levels were above therapeutic ranges. Conclusions:Community interventions are urgently needed in rural communities and should specifically target households nucleus on early malaria fever recognition and provision of recommended antimalarials for the sick underfive children. However, sadly, there was an increase in underweight and undernourishment in the study areas, probably because of malaria in the area and poverty which are associated with poor nutrition in these youngsters.

  15. [Comparison of efficacy of chloroquine versus sulfadoxine-pyrimethamine in malaria prevention in pregnant women in the Toamasina region (Madagascar)].

    Science.gov (United States)

    Randriambelomanana, J A; Rakotoarisoa, H; Herinirina, S A; Zafindravola, B A; Andrianampanalinarivo, H R

    2011-10-01

    Malaria still represents a great cause of death in sub-Saharan African areas, mainly among pregnant women. We conducted this prospective study during two years in a malaria-endemic stable region in the east of Madagascar (Toamasina) with an aim to compare the efficacy of weekly chloroquine (CQ) and the use of intermittent presumptive treatment by sulfadoxine-pyrimethamine (SP). 519 pregnant women were included in this study (CQ = 285; SP = 256). Socio-demographical characteristics of each group were identical. We found more peripheral parasitemia (CQ = 8.07% vs SP = 2.73%; P = 0.0068) and severe malaria in the CQ group (CQ = 1.75% vs SP = 0%; P = 0.0332). Anemia was more frequent in the CQ group (CQ = 4.21% vs SP = 0.35%; P = 0.0038). Placental infestation rate was also higher in the CQ group (CQ = 7.01% vs SP = 0.39%; P = 0.00001). Low birth weight and fetal death were lower in the SP group respectively [(CQ = 4.21% vs SP = 0.78%; P = 0.0121) and (CQ = 1.75%vs SP = 0%; P = 0.0332)].

  16. Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal

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    Adamou Salissou

    2014-01-01

    Full Text Available Chloroquine (CQ resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56–118 and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance.

  17. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

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    Mikus Gerd

    2006-10-01

    Full Text Available Abstract The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB has a similar mode of action as chloroquine (CQ and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003. Three serious adverse events (SAE occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%] and 24% [95% CI (19.4%, 28.3%], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

  18. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

    Science.gov (United States)

    Meissner, Peter E; Mandi, Germain; Coulibaly, Boubacar; Witte, Steffen; Tapsoba, Théophile; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, Wolfgang; Jahn, Albrecht; Walter-Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, Klaus-Dieter; Schirmer, R Heiner; Kouyaté, Bocar; Müller, Olaf

    2006-01-01

    The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa. PMID:17026773

  19. Assessment of Therapeutic Response of Plasmodium vivax and Plasmodium falciparum to Chloroquine in a Malaria Transmission Free Area in Colombia

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    Castillo Carmen Manuela

    2002-01-01

    Full Text Available In order to determine the frequency of therapeutic failures to chloroquine (CQ in patients with malaria due to either Plasmodium falciparum or P. vivax, and to explore the usefulness of a malaria-free city as a sentinel site to monitor the emergence of drug resistance, 53 patients (44 infected with P. vivax and 9 with P. falciparum were evaluated at the Laboratory of Parasitology, Universidad del Valle in Cali, Colombia. Patients received 25 mg/kg of CQ divided in three doses over 48 h; they were followed during 28 days according to WHO/PAHO protocols. While therapeutic failures to CQ in the P. vivax group were not detected, the proportion of therapeutic failures in the P. falciparum group was high (78% and consistent with the reports from endemic areas in Colombia. The diverse origin of cases presenting therapeutic failure confirmed that P. falciparum resistant to CQ is widespread in Colombia, and further supports the change in the national antimalarial drug scheme. Monitoring of drug resistance in malaria free areas would be useful to identify sites requiring efficacy evaluation, and in some situations could be the most appropriate alternative to collect information from endemic areas where therapeutic efficacy studies are not feasible.

  20. In vivo and in vitro Plasmodium falciparum Resistance to Chloroquine, Amodiaquine and Quinine in the Brazilian Amazon

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    Aluisio Augusto Cotrim SEGURADO

    1997-03-01

    Full Text Available In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4- aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimensResistência in vivo e in vitro do Plasmodium falciparum à cloroquina, amodiaquina e quinino na Amazônia Brasileira. Com o propósito de avaliar a resistência do Plasmodium falciparum às drogas antimaláricas, rotineiramente empregadas no Brasil, os autores acompanharam dez pacientes com malária falciparum adquirida na Amazônia brasileira. Os pacientes foram submetidos a estudo in vivo de sensibilidade a drogas, após tratamento com derivados 4-aminoquinoleínicos (cloroquina e amodiaquina ou quinino. A absorção das

  1. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    Science.gov (United States)

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2015-11-02

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.

  2. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    Science.gov (United States)

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2016-01-01

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance. PMID:26525783

  3. 间日疟原虫氯喹抗性研究进展%Research progress on Plasmodium vivax chloroquine resistance

    Institute of Scientific and Technical Information of China (English)

    李江艳; 李倩; 方强

    2014-01-01

    Malaria remains a serious public health problem,especially in developing countries. With the deepening of the un-derstanding of vivax malaria,Plasmodium vivax is also attracting more and more attention. An effective drug treatment is the foun-dation of controlling or even eliminating malaria. In recent years,more and more reports of chloroquine-resistance Plasmodium vivax have been reported. Plasmodium vivax chloroquine resistance has been a focus problem in vivax malaria prevention and treat-ment. In this paper,the research progress on distribution situation,detection methods and molecular markers of Plasmodium vivax chloroquine resistance is summarized.%疟疾仍然是一个严重危害人类健康的公共卫生问题,尤其多见于发展中国家。随着认识的深入,间日疟也获得越来越多的重视。有效的药物治疗是控制疟疾甚至消除疟疾的基石,近年来已有越来越多的间日疟原虫氯喹抗性报道,间日疟原虫氯喹抗性已成为间日疟防治中一个备受关注的问题。本文就间日疟原虫氯喹抗性的分布现状、体内外检测方法和分子检测标志物研究进展进行初步总结。

  4. The single crystal X-ray structure of β-hematin DMSO solvate grown in the presence of chloroquine, a β-hematin growth-rate inhibitor

    Science.gov (United States)

    Gildenhuys, Johandie; le Roex, Tanya; Egan, Timothy J.; de Villiers, Katherine A.

    2012-01-01

    Single crystals of solvated β-hematin were grown from a DMSO solution containing the antimalarial drug chloroquine, a known inhibitor of β-hematin formation. In addition, a kinetics study employing biomimetic lipid-water emulsion conditions was undertaken to further investigate the effect of chloroquine and quinidine on the formation of β-hematin. Scanning electron microscopy shows that the external morphology of the β-hematin DMSO solvate crystals is almost indistinguishable from that of malaria pigment (hemozoin) and single crystal X-ray diffraction confirms the presence of μ-propionato coordination dimers of iron(III) protoporphyrin IX. The free propionic acid functional groups of adjacent dimers hydrogen bond to included DMSO molecules, rather than forming carboxylic acid dimers. The observed exponential kinetics were modeled using the Avrami equation, with an Avrami constant equal to 1. The decreased rate of β-hematin formation observed at low concentrations of both drugs could be accounted for by assuming a mechanism of drug adsorption to sites on the fastest growing face of β-hematin. This behavior was modeled using the Langmuir isotherm. Higher concentrations of drug resulted in decreased final yields of β-hematin, and an irreversible drug-induced precipitation of iron(III) protoporphyrin IX was postulated to account for this. The model permits determination of the equilibrium adsorption constant (Kads). The values for chloroquine (log Kads = 5.55 ± 0.03) and quinidine (log Kads = 4.92 ± 0.01) suggest that the approach may be useful as a relative probe of the mechanism of action of novel antimalarial compounds. PMID:23253048

  5. The efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine for malaria treatment in rural Eastern Sudan: the interrelation between resistance, age and gametocytogenesis

    DEFF Research Database (Denmark)

    A-Elbasit, Ishraga E; Elbashir, Mustafa I; Khalil, Insaf F;

    2006-01-01

    OBJECTIVE: To compare the efficacy of sulfadoxine-pyremethamine (SP)+chloroquine (CQ) combination treatment against falciparum malaria with SP treatment alone. METHOD: In-vivo study of 254 patients with uncomplicated Plasmodium falciparum malaria in rural eastern Sudan, where the population is semi......-immune. RESULTS: Sulfadoxine-pyremethamine treatment alone cured 68.3% (41/60) and SP+CQ cured 63.4% (123/194). Early and late treatment failures occurred in both treatment groups. Host age (as a marker for immunity) and parasite gametocytogenesis (as a marker for transmissibility) were significantly associated...

  6. Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT

    DEFF Research Database (Denmark)

    Dittrich, Sabine; Alifrangis, Michael; Stohrer, Jörg M;

    2005-01-01

    OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry...... the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which...... is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South...

  7. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Ronn Anita

    2011-08-01

    Full Text Available Abstract Background In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1 therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma. Methods A monoclonal antibody (MAb that reacts with the N-side chain of the CQ molecule was prepared by use of a CQ analogue. A specific and reliable ELISA for detection of CQ was developed. The developed assay was validated by measuring CQ in tablets sold in Denmark, India and Sudan. Furthermore, kinetics of CQ concentrations in plasma of four volunteers, who ingested two tablets of Malarex® containing, 250 mg CQ base, were measured before drug intake, three hours later and thereafter at days 1, 3, 7, 14, 21 and 28. The same plasma samples were simultaneously measured by high performance liquid chromatography (HPLC. Results The ELISA proved an easy-to-handle and very sensitive tool for the detection of CQ with a lower limit of detection at 3.9 ng/ml. ELISA levels of CQ in plasma showed high agreement with the levels obtained by HPLC (r = 0.98. The specificity in the negative control group was 100%. Conclusion The developed ELISA can be used for quality screening of CQ in pharmaceutical formulations and for drug monitoring in malaria and in other infectious diseases, such as HIV, where CQ proved to be an effective therapeutic agent. The methodology has been exploited to develop monoclonal

  8. Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology

    Directory of Open Access Journals (Sweden)

    Felger Ingrid

    2010-10-01

    Full Text Available Abstract Background Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI. The analysis of single nucleotide polymorphisms (SNPs in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. Methods The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. Results The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. Conclusion This work provides the first insight into drug resistance markers of P. falciparum in the SI. The

  9. Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

    Science.gov (United States)

    Colina-Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; de Oliveira, Clayton Rodrigues; Graminha, Angélica E; Maia, Pedro Ivo da S; Deflon, Victor M; Ferreira, Antonio G; Cominetti, Marcia Regina; Batista, Alzir A

    2015-12-01

    The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.

  10. Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

    Science.gov (United States)

    Colina-Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; de Oliveira, Clayton Rodrigues; Graminha, Angélica E; Maia, Pedro Ivo da S; Deflon, Victor M; Ferreira, Antonio G; Cominetti, Marcia Regina; Batista, Alzir A

    2015-12-01

    The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin. PMID:26277415

  11. The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna

    DEFF Research Database (Denmark)

    Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

    2011-01-01

    The uptake and accumulation of most electrolytes will change with pH because of the different speciation states of these compounds at various pH. Non-ionized compounds will partition into fatty and organic phases (such as cell membranes) more readily than the corresponding charged compounds....... The toxicity of chloroquine was tested on Daphnia magna using the standard Organisation for Economic Co-operation and Development acute toxicity test modified to accommodate testing at pH levels of 7, 8, and 9. Increasing toxicity was seen at higher pH. The results of the current study confirm...... that the toxicity of weak bases with intermediate pKa values is higher at high pH levels....

  12. Sulfadoxine-pyrimethamine monotherapy in Tanzanian children gives rapid parasite clearance but slow fever clearance that is improved by chloroquine in combination therapy

    DEFF Research Database (Denmark)

    Tarimo, D S; Minjas, J N; Bygbjerg, I C

    2002-01-01

    paracetamol (PCM) (n=38) in children with uncomplicated malaria. Over 72 h, there were eight (20.5%) treatment failures in the CQ group but none in the other groups. Although not significant (P > 0.1), irrespective of resistance CQ alone had a shorter median survival time to fever clearance than SP alone (54......Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage...... vs. 60 h). SP plus CQ had a highly significantly shorter median survival time to fever clearance than SP alone (48 vs. 60 h) (P

  13. Malária falciparum resistente à cloroquina e ao Fansidar R tratada com minociclina Minocycline treatment of chloroquine-and Fansidar R-resistant falciparum malarial

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    José J. Ferraroni

    1983-08-01

    Full Text Available Em abril de 1978 uma infecção malárica causada por Plasinodium falciparum foi diagnosticada em um paciente adulto do sexo masculino, nativo da Amazônia brasileira. O parasito foi resistente in vitro à cloroquina e in vivo à associação pirimetamina + sulfadoxina (FansidarR. O paciente foi tratado com minociclina (MinomaxR; contudo, sua resposta imune ao parasito pode ter tido um importante papel na eficácia do tratamento com a minociclina.In April 1978, a Plasmodium falciparum infection was diagnosed in an adult male in Brazilian Amazonia. The parasite was resistant in vitro to chloroquine and resistent in vivo to pyrimethamine-sulfadoxine (FansidarR. The patient was successfully treated with minocycline (MinomaxR; however, his immune response to the parasite may have played an important role in the efficacy of the minocycline treatment.

  14. High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan

    DEFF Research Database (Denmark)

    A-Elbasit, I E; Khalil, I F; Elbashir, M I;

    2008-01-01

    -malarial drug resistance. In this study, malaria patients treated with SP alone (60) and SP with CQ (194) had a total treatment failure (TF) of 35.4%, with no difference between the two arms. The polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) method was used to identify polymorphisms......Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti......, 50%; TF 55%) were not associated with TF. In contrast to other studies in Africa, the triple 51I/59R/108N mutation was rare (0.6%). In addition, the pfcrt CVIET haplotype (93%) was found to be associated with the CICNI/SGEAA haplotype. Finally, these data represent a baseline for SP resistance...

  15. Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei

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    Promise Madu Emeka

    2014-01-01

    Full Text Available Background: The aim of the study was to investigate the effects of dietary combination of Nigella sativa seed and oil extracts with chloroquine (CQ, and how these combinations enhance CQ efficacy in mice infected with Plasmodium berghei and their survival rates. Materials and Methods: Chloroquine sensitive P. berghei, NK65 strain was used for the study. This was passaged intraperitoneally into albino mice with a 0.2ml standard inoculum consisting of 10 6 parasitized erythrocyte suspension in phosphate buffer solution (PBS. Parasitaemia was ascertained by microscopical examination of blood films under oil immersion at X100 magnification. Results: Nigella sativa seed in feed (NSSF, NSSF + CQ on day 4, produced 86.1% and 86.0% suppression respectively, while Nigella sativa oil extract in feed (NSOF and in combination with CQ had 86.0% and 99.9% suppression respectively. The degree of suppression with the combination was significantly higher compared to CQ alone (P < 0.001 (36.1%. Complete parasitaemia clearance was obtained on the 20 th and 15 th day of treatment for NSSF, NSSF + CQ respectively, while that for NSOF and NSOF + CQ was on days 26 and 12 respectively. For CQ parasite clearance was 12 days with treatment. Also, the combinastion of 10 mg/kg Nigella sativa oil treatment injected intraperitoneally with oral CQ produced very significant parasite suppression (P < 0.0001 (93%. Survival rate in NSSF and NSOF and in combination with CQ groups was 100 and 60.0% for CQ alone. Conclusion : sThis study shows that the use of Nigella sativa seed and oil extract as dietary supplements in combination with CQ has a potential in enhancing the efficacy of CQ and could be of benefit in management of malaria.

  16. Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei

    Science.gov (United States)

    Emeka, Promise Madu; Badger-Emeka, Lorina Ineta; Eneh, Chiamaka Maryann; Khan, Tahir Mahmood

    2014-01-01

    Background: The aim of the study was to investigate the effects of dietary combination of Nigella sativa seed and oil extracts with chloroquine (CQ), and how these combinations enhance CQ efficacy in mice infected with Plasmodium berghei and their survival rates. Materials and Methods: Chloroquine sensitive P. berghei, NK65 strain was used for the study. This was passaged intraperitoneally into albino mice with a 0.2ml standard inoculum consisting of 106 parasitized erythrocyte suspension in phosphate buffer solution (PBS). Parasitaemia was ascertained by microscopical examination of blood films under oil immersion at X100 magnification. Results: Nigella sativa seed in feed (NSSF), NSSF + CQ on day 4, produced 86.1% and 86.0% suppression respectively, while Nigella sativa oil extract in feed (NSOF) and in combination with CQ had 86.0% and 99.9% suppression respectively. The degree of suppression with the combination was significantly higher compared to CQ alone (P < 0.001) (36.1%). Complete parasitaemia clearance was obtained on the 20th and 15th day of treatment for NSSF, NSSF + CQ respectively, while that for NSOF and NSOF + CQ was on days 26 and 12 respectively. For CQ parasite clearance was 12 days with treatment. Also, the combinastion of 10 mg/kg Nigella sativa oil treatment injected intraperitoneally with oral CQ produced very significant parasite suppression (P < 0.0001) (93%). Survival rate in NSSF and NSOF and in combination with CQ groups was 100 and 60.0% for CQ alone. Conclusions: This study shows that the use of Nigella sativa seed and oil extract as dietary supplements in combination with CQ has a potential in enhancing the efficacy of CQ and could be of benefit in management of malaria. PMID:24991115

  17. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    Science.gov (United States)

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  18. Factors associated with chloroquine induced pruritus during malaria treatment in Mozambican University students Factores asociados a la aparición de prurito por cloroquina durante el tratamiento de la malaria en estudiantes universitarios de Mozambique

    Directory of Open Access Journals (Sweden)

    Helena Gama

    2009-08-01

    Full Text Available Introduction: It has been suggested that reductions in chloroquine use may be followed by a resurgence of chloroquine-susceptible falciparum malaria, and chloroquine might once again be an effective treatment choice, which renews the importance of aspects related to its use and misuse. Therefore, we aimed to estimate the prevalence of chloroquine-induced pruritus and to identify risk factors for its occurrence in Mozambican University students. Methods: A cross-sectional study was conducted at a private University in Maputo. Students were approached in the classrooms to complete a self-administered questionnaire covering sociodemographic characteristics, number of previous malaria episodes, utilization of antimalarial drugs, and life prevalence of chloroquine induced pruritus. Results: Among 795 respondents, 77.4% (601/777 reported at least one malaria episode and 73.2% (542/740 had used chloroquine before. The life-prevalence of chloroquine-induced pruritus was 30.1% (158/525. Pruritus tended to be more frequent when chloroquine was used for treatment compared with prophylaxis only (31.2% vs. 10.3%, pIntroducción: Se ha sugerido que la reducción en el uso de la cloroquina puede derivar en el resurgimiento de la malaria falciparum sensible a la cloroquina, por lo que ésta puede volver a ser un tratamiento efectivo de elección, renovando la importancia de aspectos relacionados con su uso y su mal uso. Se pretende estimar la prevalencia de prurito inducido por cloroquina e identificar los factores de riesgo asociados a su ocurrencia en estudiantes universitarios de Mozambique. Métodos: Se realizó una encuesta transversal en una Universidad privada de Mozambique. Los estudiantes fueron abordados en las aulas para completar un cuestionario autoadministrado, que contenía datos sociodemográficos e información sobre el número de episodios previos de malaria, la utilización de fármacos antipalúdicos y la prevalencia de prurito inducido por

  19. Identification of chloroquine resistance Pfcrt-K76T and determination of Pfmdr1-N86Y copy number by SYBR Green I qPCR

    Institute of Scientific and Technical Information of China (English)

    Addimas; Tajebe; Mulugeta; Aemero; Kimani; Francis; Gabriel; Magoma

    2015-01-01

    Objective:To identify prevalence of chloroquine resistance point mutation at(Pfcrt,K76T)and(Pfindr1.N86Y) copy number variation.Methods:SYBR Green I based real time PCR was used.One hundred and thirty-three samples were analyzed for(Pfcrt,K76T) and(Pfmdr1.N86Y) copy number from dried blood spot.Parasite DNA was extracted using high pure DNA preparation kit.The amplification of DNA was done by using AccuPower 2* GreenStar ’’ qPCR Master mix.For quantification purpose a new primer pair was designed for 178 base pair template from complete genome sequence of Plasmodium falciparum strain 3D7 at NCBI.Absolute quantification method was used to determine the Pfmdr1-N86 Y copy number variations.Standard curve was built from strain3D7 gDNA since it has single copy of Pfindr1 per haploid genome.The known positive controls with single and multi-copy number of Pfindr1 gene were included in each experiment.The copy number ratio of the samples to the standard calibrator was made to obtain the fold difference among the samples with respect to copy number variation.Results:Out of 133 samples 73(54.89%) were confirmed as mutant(Pfcrt,76T) and the remaining 60(45.11%) were genotyped as wild type(Pfcrt,K76).The(Pfindr1.N86Y) copy number variation was determined for 133 clinical samples.Out of these samples 61(45.86%)had single copy and the remaining 72(54.14%) had multi-copy numbers higher than 1.5 copies per genome.Thirty-four(25.56%) multi-copies were between 1.5 and 2.5 copies per genome while 38(28.57%) were more than 2.5 copies per genome.The minimum and maximum copies per genome were 0.474 and 4.741.respectively.Conclusions:The study showed high prevalence level and fixation of Pfcrt.76 T mutation after chloroquine withdrawal.The prevalence of Pfindr1 copy number variant suggested that the presence of modulating factor for emergence of Plasmodium falciparum strains with higher copy numbers.However,the prevalence level was not statistically significant.

  20. Therapeutic Assessment of Chloroquine-Primaquine Combined Regimen in Adult Cohort of Plasmodium vivax Malaria from Primary Care Centres in Southwestern India

    Science.gov (United States)

    Saravu, Kavitha; Kumar, Rishikesh; Ashok, Herikudru; Kundapura, Premananda; Kamath, Veena; Kamath, Asha; Mukhopadhyay, Chiranjay

    2016-01-01

    Background Several reports of chloroquine treatment failure and resistance in Plasmodium vivax malaria from Southeast Asian countries have been published. Present study was undertaken to assess the efficacy of chloroquine-primaquine (CQ-PQ) combined regimen for the treatment of P. vivax malaria patients who were catered by the selected primary health centres (PHCs) of Udupi taluk, Udupi district, Karnataka, India. Method Five PHCs were selected within Udupi taluk based on probability proportional to size. In-vivo therapeutic efficacy assessment of CQ (1500 mg over three days) plus PQ (210 mg over 14 days) regimen was carried out in accordance with the World Health Organization’s protocol of 28 days follow-up among microscopically diagnosed monoinfection P. vivax cohort. Results In total, 161 participants were recruited in the study of which, 155 (96.3%) participants completed till day 28 follow-up, fully complied with the treatment regimen and showed adequate clinical and parasitological response. Loss to follow up was noted with 5 (3.1%) participants and non-compliance with treatment regimen occurred with one participant (0.6%). Glucose-6-phosphate dehydrogenase deficiency (G6PDd, <30% of normal mean activity) was noted among 5 (3.1%) participants and one of them did develop PQ induced dark-brown urination which subsided after PQ discontinuation. G6PDd patients were treated with PQ 45 mg/week for eight weeks while PQ was discontinued in one case with G6PD 1.4 U/g Hb due to complaint of reddish-brown coloured urine by 48 hours of PQ initiation. Nested polymerase chain reaction test revealed 45 (28%) cases as mixed (vivax and falciparum) malaria. Conclusions The CQ-PQ combined regimen remains outstandingly effective to treat uncomplicated P. vivax malaria in Udupi taluk and thus it should continue as first line regimen. For all P. vivax cases, G6PD screening before PQ administration must be mandatory and made available in all PHCs. PMID:27315280

  1. Therapeutic Assessment of Chloroquine-Primaquine Combined Regimen in Adult Cohort of Plasmodium vivax Malaria from Primary Care Centres in Southwestern India.

    Directory of Open Access Journals (Sweden)

    Kavitha Saravu

    Full Text Available Several reports of chloroquine treatment failure and resistance in Plasmodium vivax malaria from Southeast Asian countries have been published. Present study was undertaken to assess the efficacy of chloroquine-primaquine (CQ-PQ combined regimen for the treatment of P. vivax malaria patients who were catered by the selected primary health centres (PHCs of Udupi taluk, Udupi district, Karnataka, India.Five PHCs were selected within Udupi taluk based on probability proportional to size. In-vivo therapeutic efficacy assessment of CQ (1500 mg over three days plus PQ (210 mg over 14 days regimen was carried out in accordance with the World Health Organization's protocol of 28 days follow-up among microscopically diagnosed monoinfection P. vivax cohort.In total, 161 participants were recruited in the study of which, 155 (96.3% participants completed till day 28 follow-up, fully complied with the treatment regimen and showed adequate clinical and parasitological response. Loss to follow up was noted with 5 (3.1% participants and non-compliance with treatment regimen occurred with one participant (0.6%. Glucose-6-phosphate dehydrogenase deficiency (G6PDd, <30% of normal mean activity was noted among 5 (3.1% participants and one of them did develop PQ induced dark-brown urination which subsided after PQ discontinuation. G6PDd patients were treated with PQ 45 mg/week for eight weeks while PQ was discontinued in one case with G6PD 1.4 U/g Hb due to complaint of reddish-brown coloured urine by 48 hours of PQ initiation. Nested polymerase chain reaction test revealed 45 (28% cases as mixed (vivax and falciparum malaria.The CQ-PQ combined regimen remains outstandingly effective to treat uncomplicated P. vivax malaria in Udupi taluk and thus it should continue as first line regimen. For all P. vivax cases, G6PD screening before PQ administration must be mandatory and made available in all PHCs.

  2. Perception of chloroquine efficacy and alternative treatments for uncomplicated malaria in children in a holoendemic area of Tanzania: implications for the change of treatment policy

    DEFF Research Database (Denmark)

    Tarimo, D S; Minjas, J N; Bygbjerg, I C

    2001-01-01

    of fever. It was hypothesized that the long experience with CQ and its antipyretic effect (lacking in S/P) might impede acceptance of S/P for wider use as first-line drug. Malarial fevers in children were most commonly treated with CQ (92.8%), followed by quinine (60.7%) and S/P (28.7%). A 63.2% knew......Prior to policy change from chloroquine (CQ) to sulphadoxine/pyrimethamine (S/P; Fansidar) we assessed the perception of CQ efficacy and the alternative treatment options for malaria in children among parents/guardians (N=527) of under-fives attending first level health facilities on account...... and proven CQ failures in first level health facilities and the district hospital. S/P was judged to be more effective than quinine, but too strong for children, and was the least known drug in the study area. All formulations of S/P cost more per dose for a child and an adult than CQ. The implications...

  3. Treatment of erythrocytes with the 2-cys peroxiredoxin inhibitor, Conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine.

    Directory of Open Access Journals (Sweden)

    Mariana Brizuela

    Full Text Available The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2, which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl-1,4-dioxide-quinoxaline; BBMQ, has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ, an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

  4. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

    Science.gov (United States)

    Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

    2016-01-25

    The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes.

  5. The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.

    Science.gov (United States)

    Seo, Bo-Ra; Lee, Sook-Jeong; Cho, Kyung Sook; Yoon, Young Hee; Koh, Jae-Young

    2015-12-01

    Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers. PMID:26453000

  6. Alteração da camada de fibras nervosas da retina em usuários crônicos de cloroquina Retinal nerve fiber layer alteration in chronic users of chloroquine

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    Daniela de Almeida Lyra Antunes

    2005-04-01

    Full Text Available OBJETIVOS: Avaliar a camada de fibras nervosas da retina (CFN por meio da polarimetria a laser, em pacientes em uso crônico de cloroquina. MÉTODOS: Foram estudados 44 olhos de 22 pacientes em uso de cloroquina por doenças reumatológicas, por pelo menos um ano. Como controle, foram incluídos vinte indivíduos sem uso de cloroquina com idade, gênero e raça similares. Foram excluídos os pacientes que apresentavam história familiar de hipertensão ocular ou glaucoma. Ambos os olhos foram submetidos à análise da camada de fibras nervosas da retina, com o aparelho GDx® Nerve Fiber Analyser, pelo mesmo examinador. RESULTADOS: Nos usuários crônicos de cloroquina, verificou-se alteração em mais de dois parâmetros do GDx em 28 olhos (63,6%. Ocorreu também alteração no gráfico "Deviation from normal" com perda de fibras nervosas em 11 olhos (25%. Quando comparado com o grupo controle, os parâmetros que demonstraram diferença estatisticamente significante foram: Superior Ratio, Inferior Ratio, Superior Nasal, Elipse Modulation, The Number, Superior Average e Superior Integral. Houve também associação estatisticamente significante entre o tempo de uso de cloroquina e perda da CFN. CONCLUSÕES: Comprovou-se a associação entre o uso crônico da cloroquina e a alteração da CFN detectada pelo GDx. Desta forma, esses resultados podem contribuir para o diagnóstico precoce da perda de fibras nervosas na retinopatia por cloroquina.PURPOSES: To evaluate the retina nerve fiber layer by laser polarimetry in patients in chronic use of chloroquine. METHODS: Forty-four eyes of twenty-two patients were studied. These were in use of chloroquine due to rheumatic diseases during at least one year. As a control group, twenty patients without use of chloroquine with similar characteristics (age, gender and race were included. Patients who had a family history of ocular hypertension or glaucoma were not included in this group. Both eyes were

  7. Complicações oculares da terapêutica com a cloroquina e derivados Ocular complications of chloroquine and derivatives therapy

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    Augusto Cézar Lacava

    2010-08-01

    gastrointestinal, nervous and skeletal muscular systems and the skin. Ocular adverse reactions are: photophobia, cornea verticillata, poliosis, cataract, extraocular muscle palsy, anterior uveitis, toxic maculopathy and optical neuritis. PURPOSE: Bibliography review of complications due to the use of chloroquine and its derivatives. To analyze the current practice and propedeutics' evolution. To suggest practical managements for early toxicity signs. METHODS: Bibliographic review through research on MEDLINE, PUBMED, LILACS and SciELO database. DISCUSSION: All exams that can be used to screen ocular adverse reactions are described, such as: complete ophthalmologic exam, with emphasis on biomicroscopy and indirect binocular ophthalmoscopy, computerized visual field, Amsler grid testing and color vision testing, electrophysiological exams, polarimetry and optical coherence tomography. A description of maculopathy is presented, focusing on epidemiology, risk factors, histopathology and propedeutics. Chemical structure and the differences between 4-aminoquinolone derivatives are described. CONCLUSION: All patients using chloroquine and its derivatives must be followed-up and documented since the beginning of the therapy until they reach a cumulative dose above 100 grams. The higher the cumulative dose, the more we must be concerned with patient follow-up.

  8. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

    Science.gov (United States)

    Meissner, Peter E; Mandi, Germain; Witte, Steffen; Coulibaly, Boubacar; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, Wolfgang; Jahn, Albrecht; Sanon, Mamadou; Tapsoba, Théophile; Walter-Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, Klaus-Dieter; Schirmer, Heiner; Kouyaté, Bocar; Müller, Olaf

    2005-01-01

    Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. Methods In this hospital-based randomized controlled trial, 226 children (6–59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. Results No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. Conclusion MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs. PMID:16179085

  9. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

    Science.gov (United States)

    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

  10. Chloroquine for the maintenance of remission of autoimmune hepatitis: results of a pilot study Cloroquina para manutenção da remissão da hepatite auto-imune: resultado de estudo piloto

    Directory of Open Access Journals (Sweden)

    Marcos Mucenic

    2005-12-01

    Full Text Available BACKGROUND: Due to the risks related to long-term treatment with prednisone and azathioprine, most clinicians try to withdraw these drugs when patients with autoimmune hepatitis are in remission. However, there is a high probability of relapse, and most patients end up receiving maintenance treatment. AIM: To evaluate the safety and efficacy of maintenance treatment with chloroquine in the prevention of autoimmune hepatitis relapses. METHODS: Classical treatment was stopped after achievement of biochemical and histological remission of autoimmune hepatitis. Chloroquine diphosphate, 250 mg daily, was given for at least 12 months or until the occurrence of relapses defined by levels of aminotransferases at least twice the upper normal values. RESULTS: Fourteen patients were consecutively treated and compared with 18 historical controls. There was a 6.49 (1.38-30.30 greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; 0.031. CONCLUSIONS: The group treated with chloroquine had a lower frequency of relapses. Chloroquine was safe in patients with autoimmune hepatitis and hepatic cirrhosis without decompensation, on 250 mg daily up to 2 years. These preliminary results provide a basis for upcoming controlled studies comparing chloroquine with placebo or for maintenance treatment with prednisone and/or azathioprine for the prevention of autoimmune hepatitis relapses.RACIONAL: Em razão dos riscos relacionados ao tratamento prolongado com prednisona e azatioprina, tenta-se a retirada dessas drogas em pacientes com hepatite auto-imune em remissão. Como há alta taxa de recidiva, a maioria dos pacientes recebe tratamento por tempo indefinido. OBJETIVO: Avaliar a segurança e a eficácia do tratamento de manutenção com cloroquina na prevenção de recidiva da hepatite auto-imune. MÉTODOS: O tratamento convencional foi suspenso após obtenção de remissão bioquímica e histol

  11. Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria

    DEFF Research Database (Denmark)

    Abacassamo, F; Enosse, S; Aponte, J J;

    2004-01-01

    of uncomplicated malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open, randomized, clinical trials. Children aged 6-59 months with axillary body temperature > or = 37.5 degrees C and non-complicated malaria were......% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up....

  12. Comparing histopathology of ICR mice infected with chloroquine-sensitive and chloroquine-resistant strains of Plasmodium berghei%伯氏疟原虫氯喹敏感株和抗性株感染ICR鼠病理变化的比较研究

    Institute of Scientific and Technical Information of China (English)

    陈克强; 宋关鸿

    2001-01-01

    目的:研究伯氏疟原虫(Plasmodium berghei)的抗药性与致病力的关系。方法:比较伯氏疟原虫氯喹敏感株(N)和抗性株(RC)感染ICR鼠的肝、脾、脑、心、肺、肾等重要脏器病理组织学的动态变化。结果:N株感染后,小鼠肝、脾有较多的疟色素沉着,肺脏呈郁血性水肿;脑微血管充血和阻塞;各脏器呈急性炎症的病理变化特点。RC株感染后,小鼠肝、脾脏的病理组织学改变与原虫血症的变化有关。肺脏呈间质性肺炎,各脏器呈慢性增生性炎症的病理变化特点。结论:N株致病力较强,感染后引起宿主死亡的主要原因是感染疟原虫的红细胞对脑微血管内皮细胞的粘附,造成微血管阻塞;RC株致病力较弱,宿主的应答反应在感染早期可能是CD4+Th1相关的迟发型超敏炎症反应,而感染后期是CD4+T h2辅助作用下的抗体依赖性的免疫应答,并在疟原虫的最后清除上起着关键性的作用。%Objective: To understand the relationship between chloroquine resistance and the virulence of Plasmodium berghei. Met hods: Dynamic changes of histopathologic features of livers, spleens, brains, hearts, lungs and kidneys of mice infected with the chloroquine-sensitive (N) and the chloroquine-resistant (RC) strains of P. berghei were compared. Results: In mice infected with the N strain, deposition of heavy hemoz oin in livers and spleens, congestive edema in lungs, and congestion and embolis m in the brain capillaries were observed. The histopathologic features revealed ac ute inflammatory reaction. In mice infected with the RC strain, histopathologic variations of livers and spleens were associated with changes of parasitemia. In terstitial pneumonia was displayed in lungs. There were chronic histopathologic changes of the organs in the mice infected with RC strain. Conclusion: The mice infected by the N strain with potent virulence die due to adher ence of

  13. Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidine-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Fernando A.; Kouznetsov, Vladimir V., E-mail: kouznet@uis.edu.co [Laboratorio de Quimica Organica y Biomolecular, Escuela de Quimica, Universidad Industrial de Santander, Bucaramanga (Colombia)

    2011-09-15

    In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N-(7-chloroquinoline-4-yl) alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidine-4-one and {sup 1}H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments. (author)

  14. Assessment of chloroquine single dose treatment of malaria due to Plasmodium vivax in Brazilian Amazon Cloroquina em dose simples no tratamento da malária por Plasmodium vivax na Amazônia brasileira

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    Ana Yecê das Neves Pinto

    2003-12-01

    Full Text Available Malaria regions of the Amazon basin have been characterized by difficult access and non-compliance of the patients to treatment. In an attempt to assess the schizonticide efficacy of chloroquine in a single dose of 600 mg, the authors realized a double-blind, placebo-controlled trial in 132 outpatients with vivax malaria. Patients were distributed into two groups: group CPLA, given chloroquine 600 mg (single dose on the first day of treatment, and two doses of placebo on second and third days. Group CHLO, given chloroquine 600 mg on first day and 450 mg on second and third day. Geometric means of the parasite density during the follow-up was similar in both groups. No differences were observed in the parasitological cure between the two groups (p = 0.442. There was clinical and parasitological efficacy in treatment of patients given a single-dose of chloroquine. This suggests that its restricted use could be indicated in remote areas of Brazilian Amazon Region, nevertheless the inadequate response of three patients indicates the need for further studies.As regiões malarígenas da Amazônia brasileira têm se caracterizado por dificuldades no acesso ao tratamento e não aceitação das drogas pelos doentes. Com objetivos de avaliar a eficácia da cloroquina em dose simples de 600 mg, os autores realizaram um ensaio clínico duplo cego, placebo controlado em 132 pacientes portadores de malária por P. vivax. Os pacientes foram distribuídos em dois grupos: grupo CPLA que recebia 600 mg de cloroquina em dose simples no primeiro dia de tratamento e duas doses de placebo no segundo e terceiro dias de tratamento. Grupo CLO que recebia 600 mg de cloroquina no primeiro dia e 450 mg no segundo e terceiro dias. A média geométrica da densidade parasitária durante o seguimento foi similar em ambos os grupos. Não houve diferenças de cura parasitológica em ambos os grupos (p = 0,442. Observou-se eficácia clínica e parasitológica nos indivíduos que

  15. Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial.

    Directory of Open Access Journals (Sweden)

    Joshua Kimani

    Full Text Available The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp with sulfadoxine-pyrimethamine (SP in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base for IPTp relative to IPTp-SP.A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days or SP (each course 1,500/75 mg SP QD for 1 day at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42. The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, 28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight. The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2% participants in the AZCQ and 342/1,445 (23.7% in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR of 1.11 (95% CI: 0.97, 1.25; p = 0.12. There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44. IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies

  16. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

    International Nuclear Information System (INIS)

    Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings

  17. High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation in Yemen: An urgent need to re-examine malaria drug policy

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    Al-Mekhlafi Hesham M

    2011-05-01

    Full Text Available Abstract Background Malaria remains a significant health problem in Yemen with Plasmodium falciparum being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR of P. falciparum isolated from Yemen based on the pfcrt T76 mutation. Methods A cross-sectional study was carried out among 511 participants from four governorates in Yemen. Blood samples were screened using microscopic and species-specific nested PCR based on the 18S rRNA gene to detect and identify Plasmodium species. Blood samples positive for P. falciparum were used for detecting the pfcrt T76 mutation using nested-PCR. Results The prevalence of pfcrt T76 mutation was 81.5% (66 of 81 isolates. Coastal areas/foothills had higher prevalence of pfcrt T76 mutation compared to highland areas (90.5% vs 71.8% (p = 0.031. The pfcrt T76 mutation had a significant association with parasitaemia (p = 0.045. Univariate analysis shows a significant association of pfcrt T76 mutation with people aged > 10 years (OR = 9, 95% CI = 2.3 - 36.2, p = 0.001, low household income (OR = 5, 95% CI = 1.3 - 19.5, p = 0.027, no insecticide spray (OR = 3.7, 95% CI = 1.16 - 11.86, p = 0.025 and not sleeping under insecticide treated nets (ITNs (OR = 4.8, 95% CI = 1.38 - 16.78, p = 0.01. Logistic regression model confirmed age > 10 years and low household income as predictors of pfcrt T76 mutation in Yemen P. falciparum isolates. Conclusions The high prevalence of pfcrt T76 mutation in Yemen could be a predictive marker for the prevalence of P. falciparum CQR. This finding shows the necessity for an in-vivo therapeutic efficacy test for CQ. P. falciparum CQR should be addressed in the national strategy to control malaria.

  18. Chloroquine aggravates Con A-induced autoimmune hepatitis%氯喹可加重Con A诱导的自身免疫性肝损伤

    Institute of Scientific and Technical Information of China (English)

    李延利; 王守杰; 唐媛; 张丽芸; 卢晓; 左大明; 陈政良

    2016-01-01

    氯喹(chloroquine,CQ)可抑制免疫反应,偶用于类风湿性关节炎、系统性红斑狼疮等自身免疫性疾病的治疗,但氯喹对自身免疫性肝炎的影响目前尚不明确.本研究拟探讨CQ对小鼠自身免疫性肝损伤的影响及可能机制.小鼠尾静脉注射Con A建立小鼠肝损伤模型,1h后,腹腔注射CQ或等体积PBS.观察小鼠生存状况,在不同时间点收集血清和肝组织,采用赖氏法检测血清谷丙转氨酶(GPT)水平;ELISA方法检测血清细胞因子IFN γ及TNF-α含量;HE染色观察肝脏病理损伤情况;免疫印迹检测小鼠肝脏自噬水平指标LC3-Ⅱ和P62.结果显示,Con A+CQ组小鼠血清中GPT水平显著高于Con A组,且病理切片染色显示Con A+CQ组肝脏损伤较Con A组更严重;Con A+CQ注射组小鼠的存活率明显低于仅注射Con A组(P<0.0001);Con A+CQ组小鼠血清中炎性细胞因子IFN-γ和TNF-α的分泌高于Con A组;CQ可抑制Con A刺激诱导的小鼠肝脏自噬水平升高.氯喹可加重Con A诱导的自身免疫性肝损伤,其机制可能是通过抑制肝脏自噬水平从而加剧小鼠肝脏损伤.

  19. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

    Directory of Open Access Journals (Sweden)

    Walter-Sack Ingeborg

    2005-09-01

    Full Text Available Abstract Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB combined with chloroquine (CQ has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. Methods In this hospital-based randomized controlled trial, 226 children (6–59 months with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days or CQ (n = 45; 25 mg/kg over three days respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs. Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. Results No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%] in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%] in the CQ-MB group. Conclusion MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.

  20. 复方地巴唑氢氯噻嗪胶囊中磷酸氯喹的杂质定性分析%The Qualitative Analysis of Impurities by Chloroquine Phosphate in Compound Bendazol and Hydrochlorothiazide Capsules

    Institute of Scientific and Technical Information of China (English)

    陈晓英

    2015-01-01

    The impurities of chloroquine phosphate in Compound bendazol and hydrochlorothiazide capsules, were identi⁃fied using high performance liquid chromatography(UV detector and two diode array detector)and mass spectrometry. Us⁃ing Luna C18 column with the mobile phase of methanol and acetic acid-2%,(υ/υ10∶90), with flow rate of 0.5 ml/min, col⁃umn temperature at room temperature,the injection volume was 20μl, the UV detection wavelength was 324nm and the DAD detection wavelength range was 200~400nm, by high performance liquid chromatography. In mass spectrometry, ESI electro⁃spray ionization was used, atomization gas pressure was 45 psi, with drying air flow rate 10 L/min and temperature 350℃and capillary voltage 3.5 kV, scaning MS. And then the second scan was carried out to the first target ion with voltage 20eV and collection range of 100-1000 m/z. UV detection results showed that the impurity peak in Compound bendazol and hydro⁃chlorothiazide capsules was similar to that in chloroquine phosphate. And the DAD detection result of the impuritie was simi⁃lar to chloroquine. The second mass scan result showed that the molecular fragments were similar to chloroquine. The impuri⁃ties generated by chloroquine phosphate in Compound bendazol and hydrochlorothiazide capsules is N-deethylation chloro⁃quine.%采用高效液相色谱法(HPLC)(紫外检测器UV和二级管阵列检测器DAD)和质谱法MS)对复方地巴唑氢氯噻嗪胶囊中磷酸氯喹所产生的杂质进行定性鉴别与归属.实验使用Luna C18色谱柱,以甲醇-2%醋酸(υ/υ10∶90)为流动相,流速0.5 mL/min,柱温为室温,进样量为20μl ,紫外检测波长为324 nm,DAD检测波长扫描范围为200~400 nm,进行高效液相色谱.质谱法则使用ESI电喷雾离子化源,雾化气压力为45 psi,干燥气流速为10 L/min,干燥气温度350℃,毛细管电压3.5 kV,扫描方式采用一级质谱全扫描,再对目标离子进

  1. Reducing costs by reducing size

    International Nuclear Information System (INIS)

    The present paper discusses briefly the many factors, including capital cost, which have to be taken into account in determining whether a series of power stations based on a small nuclear plant can be competitive with a series based on traditional large unit sizes giving the guaranteed level of supply. The 320 MWe UK/US Safe Integral Reactor is described as a good example of how the factors discussed can be beneficially incorporated into a design using proven technology. Finally it goes on to illustrate how the overall costs of a generating system can indeed by reduced by use of the 320 MWe Safe Integral Reactor rather than conventional units of around 1200 MWe. (author). 9 figs

  2. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

    Directory of Open Access Journals (Sweden)

    Gonzalez-Block Miguel A

    2005-10-01

    Full Text Available Abstract Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ with sulfadoxine-pyrimethamine (SP as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ. Research also indicated that since SP was also facing

  3. Chloroquine sensitizes cisplatin cytotoxicity in human gastric cancer xenografts%抗疟药氯喹增强胃癌裸鼠移植瘤对顺铂的化疗敏感性

    Institute of Scientific and Technical Information of China (English)

    方念; 张慧卿; 刘小梅; 何波; 万以叶; 程海涛; 谢桂生

    2014-01-01

    Objective To investigate the enhanced effect of cisplatin on chloroquine in SGC7901 xenografts. Methods The models of SGC7901 xenograft on athymic mouse were established and randomized to four groups with intraperitoneal injection of different drugs: control, cisplatin(DDP), chloroquine(CQ) and DDP+CQ. Drugs were injected once every 3 days, 10 times in all. The tumor volume were measured during the process of drug therapy. The mice were sacrificed 3 days after the last injection,and then the weight of tumor were measured. Western Blot was performed to detect the expression of beclin-1, LC3Ⅱ/Ⅰ, Caspase3 and P-gp, RT-PCR was performed to detect the expression of MDR1 mRNA. Results Compared to group control,the growth of tumor were more slowly and the tumor volume were much smaller in group DDP, the inhibition of tumor rate was 47.6%;and the expression of Beclin1 and LC3 were up-regulated. After combined with CQ, the inhibition of tumor rate was increased to 84.7%(P<0.01), and the ratio between LC3Ⅱ/Ⅰ was decreased;the expression of MDR1 and P-gp were also down-regulated. Conclusion Chloroquine can enhance the anti-tumor effect of cisplatin on gastric cancer xenografts, inhibition of autophagy and down-regulation of MDR1/P-gp expression are possibly the related mechanisms.%目的:探讨抗疟药氯喹(CQ)增强顺铂(DDP)抑制胃癌SGC7901细胞裸鼠移植瘤生长的作用。方法建立胃癌SGC7901细胞裸鼠异位移植瘤模型,将24只荷瘤鼠随机分为对照组、DDP组、CQ组和CQ+DDP组。腹腔注射给药,给药后每3日测量肿瘤体积。给药结束时处死裸鼠,剥离移植瘤,称重。Western Blot检测肿瘤组织beclin-1、LC3Ⅱ/Ⅰcaspase3和P-gp表达,RT-PCR技术检测MDR1 mRNA水平。结果与对照组相比,DDP组移植瘤生长缓慢,体积较小,抑瘤率为47.6%,而且Beclin1和LC3表达增加,LCⅠ转换LCⅡ增多。联合氯喹后,抑瘤率提高至84.7%(P<0.01),LC3

  4. Métodos diagnósticos para retinopatia induzida pelo difosfato de cloroquina nos portadores de lúpus eritematoso sistêmico Diagnostic methods for chloroquine diphosphate induced retinopathy in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Luciana Duarte Rodrigues

    2009-06-01

    Full Text Available OBJETIVOS: Avaliar diferentes métodos diagnósticos para a avaliação de pacientes portadores de lúpus eritematoso sistêmico, usuários crônicos do difosfato de cloroquina (DFC e, portanto, com alto risco para retinopatia tóxica. MÉTODOS: Foram analisados 72 olhos de 36 pacientes consecutivos, seguidos no Serviço de Reumatologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, de julho de 2007 a abril de 2008. Dados demográficos e clínicos foram avaliados com o intuito de estudar os fatores de alto risco e comparar os seguintes métodos oftalmológicos: acuidade visual, biomicroscopia da córnea, biomicroscopia do fundo, retinografia, angiofluoresceinografia da retina, campo visual macular com mira branca. RESULTADOS: Dos 36 pacientes, 34 (94,4% eram mulheres. A média de idade foi 39,9 ± 9,8 anos, com tempo de doença igual a 13,9 ± 6,6 anos. Além do uso crônico da cloroquina, os pacientes apresentaram altas doses diárias (>3 mg/kg e cumulativas. Não foi observada relação entre estes fatores de alto risco e maior prevalência de retinopatia. Foi encontrada prevalência de retinopatia igual a 38,9%, confirmada por alterações bilaterais, centrais ou paracentrais e reprodutíveis no exame de campo visual. Outros exames indicados para seguimento, como acuidade visual, biomicroscopia de fundo e angiofluoresceinografia não foram capazes de diagnosticar a maioria das alterações confirmadas pelo campo visual. CONCLUSÃO: Foi observada alta prevalência de retinopatia por cloroquina entre os pacientes com alto risco, usuários crônicos do DFC, segundo os achados do campo visual. A avaliação desses pacientes deve considerar a realização do exame de campo visual em intervalos menores que os propostos, mesmo quando não há suspeita clínica.PURPOSE: To evaluate different diagnostic methods for high risk chloroquine retinopathy due to prolonged use of chloroquine (more than 5 years by systemic

  5. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

    Science.gov (United States)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N; Mårtensson, Andreas; Rosenthal, Philip J; Dorsey, Grant; Sutherland, Colin J; Guérin, Philippe; Davis, Timothy M E; Ménard, Didier; Adam, Ishag; Ademowo, George; Arze, Cesar; Baliraine, Frederick N; Berens-Riha, Nicole; Björkman, Anders; Borrmann, Steffen; Checchi, Francesco; Desai, Meghna; Dhorda, Mehul; Djimdé, Abdoulaye A; El-Sayed, Badria B; Eshetu, Teferi; Eyase, Frederick; Falade, Catherine; Faucher, Jean-François; Fröberg, Gabrielle; Grivoyannis, Anastasia; Hamour, Sally; Houzé, Sandrine; Johnson, Jacob; Kamugisha, Erasmus; Kariuki, Simon; Kiechel, Jean-René; Kironde, Fred; Kofoed, Poul-Erik; LeBras, Jacques; Malmberg, Maja; Mwai, Leah; Ngasala, Billy; Nosten, Francois; Nsobya, Samuel L; Nzila, Alexis; Oguike, Mary; Otienoburu, Sabina Dahlström; Ogutu, Bernhards; Ouédraogo, Jean-Bosco; Piola, Patrice; Rombo, Lars; Schramm, Birgit; Somé, A Fabrice; Thwing, Julie; Ursing, Johan; Wong, Rina P M; Zeynudin, Ahmed; Zongo, Issaka; Plowe, Christopher V; Sibley, Carol Hopkins

    2014-10-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

  6. Sensitized cytotoxic effects of dexamethasone or radiation on multiple myeloma cells by chloroquine%氯喹增敏地塞米松或辐射对多发性骨髓瘤细胞的杀伤作用

    Institute of Scientific and Technical Information of China (English)

    付慧; 陶玉龙; 倪敏; 李冬洁; 沈甫明

    2016-01-01

    目的 研究氯喹(chloroquine,CQ),及CQ是否增敏化疗药物地塞米松(dexamethasone,DEX)或辐射对多发性骨髓瘤细胞株U266细胞的杀伤作用,并探讨其可能机制.方法 用细胞活性检测试剂盒(cell counting kit-8,cck8)检测CQ单药,以及CQ联用DEX对U266细胞增殖的影响,运用中效原理软件评估两药相互作用;cck8及流式细胞术分别检测CQ处理条件下辐射对U266细胞增殖和凋亡作用的改变;Western blot检测CQ合用DEX,以及CQ联合辐射对U266细胞内B细胞淋巴瘤-2(B-cellymphoma-2,Bcl-2)蛋白表达变化.结果 CQ及DEX对U266细胞的增殖抑制作用呈浓度依赖性,且CQ(3.9μmol/L)能够增强DEX(125μmol/L)对U266细胞的杀伤作用,并增加DEX降低细胞内抗凋亡蛋白Bcl-2的表达水平;不同辐射剂量(5~25 Gy)对U266细胞的生长抑制作用并无差异;CQ(1.0μmol/L)可以增加辐射对U266细胞的敏感性,诱导细胞凋亡.结论 CQ能够增敏DEX或辐射对U266细胞的杀伤作用,CQ增敏DEX的作用机制可能与抑制Bcl-2蛋白表达相关.%Objective To investigate the role and possible mechanism of combination use of chloroquine (CQ) with either dexamethasone (DEX) or radiation on multiple myeloma (MM) cell line U266 .Methods Cell viability of U266 treated with CQ alone ,or CQ combined with either DEX or radiation was measured by cell counting kit-8 (cck8) .CalcuSyn method was used to assess effect of drugs interaction .Cell viability and apoptosis of U266 pre-treated with CQ were also measured by cck8 and flow cytometry after radiation .Expression of B-cellymphoma-2 (Bcl-2) in U266 cells treated by CQ combined with DEX or radiation was determined by Western blot analysis .Results Either CQ or DEX displayed a dose dependent cell proliferation in-hibitory effect on U266 cells .Cytotoxic effect of DEX (125 μmol/L) on U266 cells was enhanced and expression of Bcl-2 pro-tein in U266 cells was decreased by combining with CQ (3 .9 μmol/L) .U266 cells were

  7. An HPLC method with diode array detector for the simultaneous quantification of chloroquine and desethylchloroquine in plasma and whole blood samples from Plasmodium vivax patients in Vietnam, using quinine as an internal standard.

    Science.gov (United States)

    Van Pham, Toi; Pham Nguyen, Phuong; Nguyen Duc Khanh, Tho; Nguyen Thanh Thuy, Nhien; Nguyen Thuy Nha, Ca; Pouplin, Thomas; Farrar, Jeremy; Thwaites, Guy E; Tran Tinh, Hien

    2016-07-01

    A sensitive, simple method for quantification of chloroquine (CQ) and desethylchloroquine (MCQ) in whole blood and plasma from Plasmodium vivax patients has been developed using HPLC with diode array detection (DAD). Solid-phase extraction on Isolute-96-CBA was employed to process 100 μL of plasma/whole blood samples. CQ, MCQ and quinine were separated using a mobile phase of phosphate buffer 25 mm, pH 2.60-acetonitrile (88:12, v/v) with 2 mm sodium perchlorate on a Zorbax SB-CN 150 × 4.6 mm, 5 μm column at a flow rate of 1.2 mL/min, at ambient temperature in 10 min, with the DAD wavelength of 343 nm. The method was linear over the range of 10-5000 ng/mL for both CQ and MCQ in plasma and whole blood. The limit of detection was 4 ng/mL and limit of quantification was 10 ng/mL in both plasma and blood for CQ and MCQ. The intra-, inter- and total assay precision were <10% for CQ and MCQ in plasma and whole blood. In plasma, the accuracies varied between 101 and 103%, whereas in whole blood, the accuracies ranged from 97.0 to 102% for CQ and MCQ. The method is an ideal technique with simple facilities and instruments, bringing about good separation in comparison with previous methods. © 2016 The Authors Biomedical Chromatography Published by John Wiley & Sons Ltd. PMID:26578224

  8. On the molecular basis of the activity of the antimalarial drug chloroquine: EXAFS-assisted DFT evidence of a direct Fe-N bond with free heme in solution

    Science.gov (United States)

    Macetti, Giovanni; Rizzato, Silvia; Beghi, Fabio; Silvestrini, Lucia; Lo Presti, Leonardo

    2016-02-01

    4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking π···π interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0-5.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe-N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies.

  9. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway.

    Science.gov (United States)

    Sun, Li; Zhang, Song; Yu, Chengyuan; Pan, Zhenwei; Liu, Yang; Zhao, Jing; Wang, Xiaoyu; Yun, Fengxiang; Zhao, Hongwei; Yan, Sen; Yuan, Yue; Wang, Dingyu; Ding, Xue; Liu, Guangzhong; Li, Wenpeng; Zhao, Xuezhu; Liu, Zhaorui; Li, Yue

    2015-12-01

    Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.

  10. In Vitro Sensitivity of Plasmodium falciparum Isolates from China-Myanmar Border Region to Chloroquine,Piperaquine and Pyronaridine%中缅边境地区恶性疟原虫对氯喹、哌喹、咯萘啶敏感性的体外测定

    Institute of Scientific and Technical Information of China (English)

    张苍林; 周红宁; 王剑; 刘慧

    2012-01-01

    目的 了解中缅边境地区恶性疟原虫(Plasmodium falciparum)对氯喹、哌喹和咯萘啶敏感性的变化.方法 2009年9~12月在中缅边境的缅甸拉咱市采集了51份恶性疟血样,采用Rieckmann体外微量测定法进行药物敏感性测定. 结果 敏感性测定结果有效的42份血样中,其恶性疟原虫对氯喹、哌喹和咯萘啶的抗性率分别为95.2%、7.1%和54.8%,半数抑制量(ID50)分别为320.5、128.2和96.0 nmol/L.在抗咯萘啶的23份血样中,对氯喹和哌喹的交叉抗性率分别为91.3% (21/23)和13.0% (3/23);抗氯喹的40份血样中,对哌喹和咯萘啶的交叉抗性率分别为7.5% (3/40)和52.5% (21/40);抗哌喹的3份血样中,对氯喹和咯萘啶的交叉抗性率均为100%.结论 在缅甸拉咱市调查点流行的恶性疟原虫对氯喹已普遍产生抗性,约半数对咯萘啶具有抗性,多数对哌喹则敏感.%Objective To assess the in vitro sensitivity of Plasmodium falciparum to chloroquine, piperaquine and pyronaridine in China-Myanmar border area. Methods Fifty-one blood specimens of P. Falcipamm isolates were collected from Laza City of Myanmar during September to December in 2009, and the sensitivity of the parasites to the drugs was detected by Rieckmann's in vitro microtest. Results Among the 42 blood samples with valid results of sensitivity test, the resistance rate to chloroquine, piperaquine and pyronaridine was 95.2%, 7.1%, and 54.8%, with a corresponding 50% inhibition dose (ID50 ) of 320.5, 128.2, and 96.0nmol/L, respectively. Pyronaridine-resistant P. Falcipamm exhibited some degree of cross-resistance to chloroquine [91.3%(21/23)] and piperaquine [13.0% (3/23)], and chloroquine-resistant P. Falciparum showed cross-resistance to piperaquine [7.5%(3/40)] and pyronaridine [52.5%(21/40) ]. High level of cross-resistance was present to chloroquine (100%) and pyronaridine (100%) in piperaquineresistant P. Falciparum. Conclusion In Laza City, P. Falciparum

  11. Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease.

    Science.gov (United States)

    Fox, Christopher; Cocchiaro, Pasquale; Oakley, Fiona; Howarth, Rachel; Callaghan, Krystena; Leslie, Jack; Luli, Saimir; Wood, Katrina M; Genovese, Federica; Sheerin, Neil S; Moles, Anna

    2016-01-01

    During chronic kidney disease (CKD) there is a dysregulation of extracellular matrix (ECM) homeostasis leading to renal fibrosis. Lysosomal proteases such as cathepsins (Cts) regulate this process in other organs, however, their role in CKD is still unknown. Here we describe a novel role for cathepsins in CKD. CtsD and B were located in distal and proximal tubular cells respectively in human disease. Administration of CtsD (Pepstatin A) but not B inhibitor (Ca074-Me), in two mouse CKD models, UUO and chronic ischemia reperfusion injury, led to a reduction in fibrosis. No changes in collagen transcription or myofibroblasts numbers were observed. Pepstatin A administration resulted in increased extracellular urokinase and collagen degradation. In vitro and in vivo administration of chloroquine, an endo/lysosomal inhibitor, mimicked Pepstatin A effect on renal fibrosis. Therefore, we propose a mechanism by which CtsD inhibition leads to increased collagenolytic activity due to an impairment in lysosomal recycling. This results in increased extracellular activity of enzymes such as urokinase, triggering a proteolytic cascade, which culminates in more ECM degradation. Taken together these results suggest that inhibition of lysosomal proteases, such as CtsD, could be a new therapeutic approach to reduce renal fibrosis and slow progression of CKD. PMID:26831567

  12. In vitro sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin antimalarials%恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物体外敏感性的研究

    Institute of Scientific and Technical Information of China (English)

    黄芳; 冯晓平; 周水森; 汤林华

    2008-01-01

    目的 测定恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物的体外敏感性. 方法 运用体外微量法与酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定青蒿琥酯、蒿甲醚及双氢青蒿素等3种青蒿素类抗疟药物对体外培养的恶性疟原虫氯喹敏感株与氯喹抗性株的体外敏感性,并比较两种方法测定的IC50值. 结果 体外微量法测定的3种药物对恶性疟原虫氯喹敏感株的IC50值依次为3.12 nmol/L、4.30 nmol/L、2.18 nmol/L,对恶性疟原虫氯喹抗性株的IC50值依次为4.31nmol/L、3.90 nmol/L、3.17 nmol/L;同时,将体外微量法与ELISA法所获的结果进行相关性分析,两种方法结果基本一致(r2=0.93,P<0.001). 结论 恶性疟原虫氯喹抗性株对青蒿素类药物无明显的交叉抗性;ELISA法可用于恶性疟原虫对抗疟药物的体外敏感性检测.%Objective To test the sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin anfimalarials. Method The responses of chloroquine sensitive and resistant P.falciparum to artemisinin antimalarials including artesunate,artemether and dihydroartemisinin were determined with Rieckmann s in vitro micro-technique and enzyme-linked immunosorbent assay(ELISA).The values of 50%inhibition of parasitemia(IC50)were compared with above two methods. Results The IC50 of artemisinin antimalarials in chloroquine sensitive P.falciparum were 3.12 nmoL/L,4.30 nmol/L,2.18 nmol/L respectively,while that in chloroquine resistant P. falciparum were 4.31nmol/L,3.90 nmol/L,3.17 nmol/L.The results obtained with both techniques were similar or identical by correlation analysis(r2=0.93,P<0.001).Conclusions There were no apparent cross-resistance of chloroquine resistant P.falciparum to artemisinin antimalarials.The ELISA test would be suitable for testing antimalarial drugs sensitivitv in vitro.

  13. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario.

    Science.gov (United States)

    Almeida, Luciana O; Goto, Renata N; Neto, Marinaldo P C; Sousa, Lucas O; Curti, Carlos; Leopoldino, Andréia M

    2015-03-01

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer.

  14. Reducing Childhood Obesity

    Science.gov (United States)

    ... Bar Home Current Issue Past Issues Reducing Childhood Obesity Past Issues / Summer 2007 Table of Contents For ... Ga. were the first three We Can! cities. Obesity Research: A New Approach The percentage of children ...

  15. Reducing Erosion and Runoff

    OpenAIRE

    Relf, Diane

    2009-01-01

    By caring for and improving your soil, you will help it absorb water more readily, reducing runoff and erosion as well as improving plant health. This publication gives the homeowner tips to help prevent runoff and erosion on their property.

  16. Reducing workers' compensation costs.

    Science.gov (United States)

    Killian, M J

    1994-01-01

    Employers can reduce their workers' compensation costs by encouraging internal communication and education before and after injuries occur. Comprehensive workers' compensation programs can be developed by integrating the management of employee benefits and workers' compensation claims. PMID:10133659

  17. Reduced Extended MHD

    Science.gov (United States)

    Morrison, P. J.; Abdelhamid, H. M.; Grasso, D.; Hazeltine, R. D.; Lingam, M.; Tassi, E.

    2015-11-01

    Over the years various reduced fluid models have been obtained for modeling plasmas, with the goal of capturing important physics while maintaining computability. Such models have included the physics contained in various generalizations of Ohm's law, including Hall drift and electron inertia. In a recent publication it was shown that full 3D extended MHD is a Hamiltonian system by finding its noncanonical Poisson bracket. Subsequently, this bracket was shown to be derivable from that for Hall MHD by a series of remarkable transformations, which greatly simplifies the proof of the Jacobi identity and allows one to immediately obtain generalizations of the helicity and cross helicity. In this poster we use this structure to obtain exact reduced fluid models with the effects of full two-fluid theory. Results of numerical computations of collisionless reconnection using an exact reduced 4-field model will be presented and analytical comparisons of mode structure of previous reduced models will be made.

  18. Reducible functional differential equations

    Directory of Open Access Journals (Sweden)

    S. M. Shah

    1985-01-01

    Full Text Available This is the first part of a survey on analytic solutions of functional differential equations (FDE. Some classes of FDE that can be reduced to ordinary differential equations are considered since they often provide an insight into the structure of analytic solutions to equations with more general argument deviations. Reducible FDE also find important applications in the study of stability of differential-difference equations and arise in a number of biological models.

  19. Reduced shear power spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Dodelson, Scott; /Fermilab /Chicago U., Astron. Astrophys. Ctr. /Northwestern U.; Shapiro, Charles; /Chicago U. /KICP, Chicago; White, Martin J.; /UC, Berkeley, Astron.

    2005-08-01

    Measurements of ellipticities of background galaxies are sensitive to the reduced shear, the cosmic shear divided by (1-{kappa}) where {kappa} is the projected density field. They compute the difference between shear and reduced shear both analytically and with simulations. The difference becomes more important an smaller scales, and will impact cosmological parameter estimation from upcoming experiments. A simple recipe is presented to carry out the required correction.

  20. 滋阴润燥生津汤联合硫酸羟化氯喹治疗干燥综合征患者的临床疗效%Oneself can Nourish dry soup Combined Sulphuric acid Hydroxyl,the Clinical Curative effect Analysis of Chloroquine Treatment of Sjogren's Syndrome

    Institute of Scientific and Technical Information of China (English)

    张宝国

    2016-01-01

    Objective To study the oneself can nourish dry soup combined sulphuric acid hydroxyl chloroquine in effect in the treatment of sjogren's syndrome.Methods Choose 80 cases of patients with sjogren's syndrome,were randomly divided into control group and the treatment group,al 40 cases,the control group given sulfuric acid hydroxyl chloroquine treatment,the treatment group in the control group on the basis of joint oneself can nourish dry soup treatment,compared two groups of therapeutic effect.Results The treatment group effective rate was 95.0%,control group was 80.0%,the treatment group is significantly higher than control group(P<0.05).Conclusion For sjogren's syndrome using oneself can nourish dry soup combined sulphuric acid hydroxyl chloroquine treatment can improve symptoms, obvious effect,have clinical application value.%目的:探讨滋阴润燥生津汤联合硫酸羟化氯喹治疗干燥综合征患者的临床疗效。方法选取80例干燥综合征患者为研究对象,按随机数字表法分为对照组与试验组,各40例,对照组患者给予硫酸羟化氯喹治疗,试验组患者在对照组基础上联合滋阴润燥生津汤治疗,对比两组患者的治疗效果。结果试验组患者治疗总有效率为95.0%,对照组为80.0%,试验组明显高于对照组(P<0.05)。结论对于干燥综合征患者采用滋阴润燥生津汤联合硫酸羟化氯喹治疗能改善临床症状,效果显著。

  1. Reducible chiral metamaterials

    CERN Document Server

    Ciattoni, Alessandro; Rizza, Carlo

    2016-01-01

    We introduce the concept of 3D reducible metamaterials whose constituent permittivity can be modelled by a factorized profile. The separated cartesian coordinates dependence, easily achieved in all-optical reconfigurable materials, allows to physically regard a reducible metamaterial as a superposition of three fictitious 1D generating media. We prove that, in the long-wavelength limit, the electromagnetic response of reducible metamaterials can be reconstructed from the properties of the 1D generating media whose interplay provides large freedom to control the electromagnetic chirality. Our approach introduces an unprecedented decomposition strategy in metamaterial science which allows the full ab-initio and flexible design of a complex 3D bianisotropic response by using 1D metamaterials as basic building blocks.

  2. Tank closure reducing grout

    Energy Technology Data Exchange (ETDEWEB)

    Caldwell, T.B.

    1997-04-18

    A reducing grout has been developed for closing high level waste tanks at the Savannah River Site in Aiken, South Carolina. The grout has a low redox potential, which minimizes the mobility of Sr{sup 90}, the radionuclide with the highest dose potential after closure. The grout also has a high pH which reduces the solubility of the plutonium isotopes. The grout has a high compressive strength and low permeability, which enhances its ability to limit the migration of contaminants after closure. The grout was designed and tested by Construction Technology Laboratories, Inc. Placement methods were developed by the Savannah River Site personnel.

  3. Reducing rotor weight

    Energy Technology Data Exchange (ETDEWEB)

    Cheney, M.C. [PS Enterprises, Inc., Glastonbury, CT (United States)

    1997-12-31

    The cost of energy for renewables has gained greater significance in recent years due to the drop in price in some competing energy sources, particularly natural gas. In pursuit of lower manufacturing costs for wind turbine systems, work was conducted to explore an innovative rotor designed to reduce weight and cost over conventional rotor systems. Trade-off studies were conducted to measure the influence of number of blades, stiffness, and manufacturing method on COE. The study showed that increasing number of blades at constant solidity significantly reduced rotor weight and that manufacturing the blades using pultrusion technology produced the lowest cost per pound. Under contracts with the National Renewable Energy Laboratory and the California Energy Commission, a 400 kW (33m diameter) turbine was designed employing this technology. The project included tests of an 80 kW (15.5m diameter) dynamically scaled rotor which demonstrated the viability of the design.

  4. Risk-reducing mastectomy.

    Science.gov (United States)

    Chiesa, Federica; Sacchini, Virgilio S

    2016-10-01

    Mastectomy rates have significantly increased over the last decades, likely due to the rising trend of risk-reducing mastectomies (RRM) in the treatment and prevention of breast cancer. Growing evidence suggests that aggressive risk-reducing surgical strategies are only justified in high-risk breast cancer situations. Notably, in this selected cohort of women, prophylactic mastectomies offer evident benefit for local and contralateral disease control, and may also provide a survival benefit. Nevertheless, the extent of the increasing frequency of this operation is not explained by the broadening of the medical indications alone. Here we analyze the current evidence regarding RRM, its clinical practice, and possible explanations for the rising phenomenon of aggressive surgical locoregional control strategies. PMID:26785281

  5. Reduced Multiplication Modules

    Indian Academy of Sciences (India)

    Karim Samei

    2011-05-01

    An -module is called a multiplication module if for each submodule of , = for some ideal of . As defined for a commutative ring , an -module is said to be reduced if the intersection of prime submodules of is zero. The prime spectrum and minimal prime submodules of the reduced module are studied. Essential submodules of are characterized via a topological property. It is shown that the Goldie dimension of is equal to the Souslin number of Spec (). Also a finitely generated module is a Baer module if and only if Spec () is an extremally disconnected space; if and only if it is a -module. It is proved that a prime submodule is minimal in if and only if for each $x\\in N,\\mathrm{Ann}(x)\

  6. Coupling Reduces Noise

    OpenAIRE

    Kia, Behnam; Kia, Sarvenaz; Lindner, John. F.; Sinha, Sudeshna; Ditto, William L.

    2014-01-01

    We demonstrate how coupling nonlinear dynamical systems can reduce the effects of noise. For simplicity we investigate noisy coupled map lattices. Noise from different lattice nodes can diffuse across the lattice and lower the noise level of individual nodes. We develop a theoretical model that explains this observed noise evolution and show how the coupled dynamics can naturally function as an averaging filter. Our numerical simulations are in excellent agreement with the model predictions.

  7. Does democracy reduce corruption?

    OpenAIRE

    Ivar Kolstad; Arne Wiig

    2011-01-01

    While democracy is commonly believed to reduce corruption, there are obvious endogeneity problems in measuring the impact of democracy on corruption. This paper addresses the endogeneity of democracy by exploiting the common observation that democracies seldom go to war against each other. We instrument for democracy using a dummy variable reflecting whether a country has been at war with a democracy in the period 1946-2009, while controlling for the extent to which countries have been at war...

  8. Awareness Reduces Racial Bias

    OpenAIRE

    Pope, Devin G.; Price, Joseph; Wolfers, Justin

    2014-01-01

    Can raising awareness of racial bias subsequently reduce that bias? We address this question by exploiting the widespread media attention highlighting racial bias among professional basketball referees that occurred in May 2007 following the release of an academic study. Using new data, we confirm that racial bias persisted in the years after the study's original sample, but prior to the media coverage. Subsequent to the media coverage though, the bias completely disappeared. We examine poten...

  9. Quantum Reduced Loop Gravity

    OpenAIRE

    Alesci, Emanuele; Cianfrani, Francesco

    2015-01-01

    Quantum Reduced Loop Gravity provides a promising framework for a consistent characterization of the early Universe dynamics. Inspired by BKL conjecture, a flat Universe is described as a collection of Bianchi I homogeneous patches. The resulting quantum dynamics is described by the scalar constraint operator, whose matrix elements can be analytically computed. The effective semiclassical dynamics is discussed, and the differences with Loop Quantum Cosmology are emphasized.

  10. Reducing volcanic risk

    Science.gov (United States)

    Decker, R.; Decker, B.

    1991-01-01

    The last two decades have brought major advances in research on how volcanoes work and how to monitor their changing habits. Geologic mapping as well as studies of earthquake patterns and surface deformation associated with underground movement of magma have given scientists a better view of the inner structure and dynamics of active volcanoes. With the next decade, the time has come to focuses more on applying this knowledge toward reducing the risk from volcanic activity on a worldwide basis. 

  11. Gradual extinction reduces Reinstatement

    Directory of Open Access Journals (Sweden)

    Youssef eShiban

    2015-09-01

    Full Text Available The current study investigated whether gradually reducing the frequency of aversive stimuli during extinction can prevent the return of fear. Thirty-one participants of a three-stage procedure (acquisition, extinction and a reinstatement test on day two were randomly assigned to a standard extinction (SE and gradual extinction (GE procedure. The two groups differed only in the extinction procedure. While the SE group ran through a regular extinction process without any negative events, the frequency of the aversive stimuli during the extinction phase was gradually reduced for the GE group. The unconditioned stimulus was an air blast (5 bar, 10 ms. A spider and a scorpion were used as conditioned stimuli. The outcome variables were contingency ratings and physiological measures (skin conductance response and startle response. There were no differences found between the two groups for the acquisition and extinction phases concerning contingency ratings, SCR, or startle response. Gradual extinction compared to standard extinction significantly reduced the return of fear in the reinstatement test for the startle response but not for skin conductance response or contingency ratings. This study was successful in translating the findings in rodent to humans. The results suggest that the gradual extinction process is suitable for increasing the efficacy of fear extinction.

  12. Reducing Iatrogenic Risks

    Science.gov (United States)

    Ely, E. Wesley; Speroff, Theodore; Pun, Brenda T.; Boehm, Leanne; Dittus, Robert S.

    2010-01-01

    ICUs are experiencing an epidemic of patients with acute brain dysfunction (delirium) and weakness, both associated with increased mortality and long-term disability. These conditions are commonly acquired in the ICU and are often initiated or exacerbated by sedation and ventilation decisions and management. Despite > 10 years of evidence revealing the hazards of delirium, the quality chasm between current and ideal processes of care continues to exist. Monitoring of delirium and sedation levels remains inconsistent. In addition, sedation, ventilation, and physical therapy practices proven successful at reducing the frequency and severity of adverse outcomes are not routinely practiced. In this article, we advocate for the adoption and implementation of a standard bundle of ICU measures with great potential to reduce the burden of ICU-acquired delirium and weakness. Individual components of this bundle are evidence based and can help standardize communication, improve interdisciplinary care, reduce mortality, and improve cognitive and functional outcomes. We refer to this as the “ABCDE bundle,” for awakening and breathing coordination, delirium monitoring, and exercise/early mobility. This evidence-based bundle of practices will build a bridge across the current quality chasm from the “front end” to the “back end” of critical care and toward improved cognitive and functional outcomes for ICU survivors. PMID:21051398

  13. Reduced Google matrix

    CERN Document Server

    Frahm, K M

    2016-01-01

    Using parallels with the quantum scattering theory, developed for processes in nuclear and mesoscopic physics and quantum chaos, we construct a reduced Google matrix $G_R$ which describes the properties and interactions of a certain subset of selected nodes belonging to a much larger directed network. The matrix $G_R$ takes into account effective interactions between subset nodes by all their indirect links via the whole network. We argue that this approach gives new possibilities to analyze effective interactions in a group of nodes embedded in a large directed networks. Possible efficient numerical methods for the practical computation of $G_R$ are also described.

  14. Reducing Outdoor Advertising

    Directory of Open Access Journals (Sweden)

    Patrice de Rendinger

    2006-05-01

    Full Text Available The fundamental concept is that public space is not a private property. So, a facade (the outer skin, the last millimeter belongs to the town, not to the owner of the building. Changing the rendering, a window, adding or removing anything from a facade requires a permission delivered by the town's authority.In places like Paris, Bordeaux, Marseilles, Lyon, Strasbourg… everywhere one can find a registrated building such as a cathedral, a castle, or a group of ancient buildings, a national administration is controlling this permission. This administration is called «historical monuments administration» and is locally lead by a specialized architect.In the late seventies, French government decided to reduce advertising on the roads and on the city walls. Advertising on the road was leading to a confusion reducing the efficacy of the roadsigns and direction signs, which is dangerous. The reduction was under control of a national administration: the ministry of equipment in charge of the roads design. Advertising on the walls with publicity boards was under control of the cities. Every city has a townplanning regulation. Many cities included forbidding advertisement boards on the walls in this regulation.A couple of firms, but mainly once (Decaux found clever to give a hand to the cities to control advertising. Decaux developed a line of bus stop shelters including advertisements and advertising panels and paid the cities the right to put rather smaller publicities on the public domain.Now Decaux is no more alone on this market and the cities are comparing offers.Marseille turned to a foreign advertising firm who pays three times the price Decaux paid… for half of the advertising surface. Freiburg erased totally the public domain advertisements, selling the tramways and bus coachwork as advertising spaces. Paris is reopening the advertising market before the end of Deacaux's contract and will pay Deacaux a huge amount

  15. Reduced Order Podolsky Model

    CERN Document Server

    Thibes, Ronaldo

    2016-01-01

    We perform the canonical and path integral quantizations of a lower-order derivatives model describing Podolsky's generalized electrodynamics. The physical content of the model shows an auxiliary massive vector field coupled to the usual electromagnetic field. The equivalence with Podolsky's original model is studied at classical and quantum levels. Concerning the dynamical time evolution we obtain a theory with two first-class and two second-class constraints in phase space. We calculate explicitly the corresponding Dirac brackets involving both vector fields. We use the Senjanovic procedure to implement the second-class constraints and the Batalin-Fradkin-Vilkovisky path integral quantization scheme to deal with the symmetries generated by the first-class constraints. The physical interpretation of the results turns out to be simpler due to the reduced derivatives order permeating the equations of motion, Dirac brackets and effective action.

  16. Reducing client waiting time.

    Science.gov (United States)

    1992-01-01

    This first issues of Family Planning (FP) Manager focuses on how to analyze client waiting time and reduce long waits easily and inexpensively. Client flow analysis can be used by managers and staff to identify organizational factors affecting waiting time. Symptoms of long waiting times are overcrowded waiting rooms, clients not returning for services, staff complaints about rushing and waiting, and hurried counseling sessions. Client satisfaction is very important in order to retain FP users. Simple procedures such as routing return visits differently can make a difference in program effectiveness. Assessment of the number of first visits, the number of revisits, and types of methods and services that the clinic provides is a first step. Client flow analysis involves assigning a number to each client on registration, attaching the client flow form to the medical chart, entering the FP method and type of visit, asking staff to note the time at each station, and summarizing data in a master chart. The staff should be involved in plotting data for each client to show waiting versus staff contact time through the use of color coding for each type of staff contact. Bottlenecks become very visible when charted. The amount of time spent at each station can be measured, and gaps in client's contact with staff can be identified. An accurate measure of total waiting time can be obtained. A quick assessment can be made by recording arrival and departure times for each client in one morning or afternoon of a peak day. The procedure is to count the number of clients waiting at 15-minute intervals. The process should be repeated every 3-6 months to observe changes. If waiting times appear long, a more thorough assessment is needed on both a peak and a typical day. An example is given of a completed chart and graph of results with sample data. Managers need to set goals for client flow, streamline client routes, and utilize waiting time wisely by providing educational talks

  17. Reducing maintenance costs

    International Nuclear Information System (INIS)

    The increasingly more expensive maintenance measures, cuts in the cost budget, and the loss of know-how on the part of vendors all require a change of policy with respect to maintenance concepts of the part of operators. This also applies to the existing valve concepts, the drives included. Under these aspects, the current drive, which is self-actuated and actuated by outside media, for a parallel-plate valve of a nomial width of 700 was reconsidered. The effort served to reduce maintenance costs and, at the same time, simplify the drive concept as well as cut back on the number of in-service inspections. Moreover, the number of active components were to be minimized and installation conditions in the plant were to be improved. When the boundary conditions to be observed with respect to process technology had been laid down, the competent technical department developed a concept of modification of the drive. A major constituent part was the demonstration of the functioning capability of the new drive under accident conditions. It was achieved mainly by an analytical approach. In the resultant drive concept, the same control valves are employed to actuate a driving cylinder by means of self-actuation or by an outside medium as a function of pressure. (orig.)

  18. Stewarding a Reduced Stockpile

    Energy Technology Data Exchange (ETDEWEB)

    Goodwin, B T; Mara, G

    2008-04-18

    The future of the US nuclear arsenal continues to be guided by two distinct drivers: the preservation of world peace and the prevention of further proliferation through our extended deterrent umbrella. Timely implementation of US nuclear policy decisions depends, in part, on the current state of stockpile weapons, their delivery systems, and the supporting infrastructure within the Department of Defense (DoD) and the Department of Energy's National Nuclear Security Administration (NNSA). In turn, the present is a product of past choices and world events. Now more than ever, the nuclear weapons program must respond to the changing global security environment and to increasing budget pressures with innovation and sound investments. As the nation transitions to a reduced stockpile, the successes of the Stockpile Stewardship Program (SSP) present options to transition to a sustainable complex better suited to stockpile size, national strategic goals and budgetary realities. Under any stockpile size, we must maintain essential human capital, forefront capabilities, and have a right-sized effective production capacity. We present new concepts for maintaining high confidence at low stockpile numbers and to effectively eliminate the reserve weapons within an optimized complex. We, as a nation, have choices to make on how we will achieve a credible 21st century deterrent.

  19. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

    International Nuclear Information System (INIS)

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer. - Highlights: • SET, UCPs and autophagy prevention are correlated. • SET action has mitochondrial involvement. • UCP2/3 may reduce ROS and prevent autophagy. • SET protects cell from ROS via UCP2/3

  20. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luciana O.; Goto, Renata N. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Neto, Marinaldo P.C. [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Sousa, Lucas O. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Curti, Carlos [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Leopoldino, Andréia M., E-mail: andreiaml@usp.br [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil)

    2015-03-06

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer. - Highlights: • SET, UCPs and autophagy prevention are correlated. • SET action has mitochondrial involvement. • UCP2/3 may reduce ROS and prevent autophagy. • SET protects cell from ROS via UCP2/3.

  1. Blocking autophagy prevents bortezomib-induced NF-κB activation by reducing I-κBα degradation in lymphoma cells.

    Directory of Open Access Journals (Sweden)

    Li Jia

    Full Text Available Here we show that bortezomib induces effective proteasome inhibition and accumulation of poly-ubiquitinated proteins in diffuse large B-cell lymphoma (DLBCL cells. This leads to induction of endoplasmic reticulum (ER stress as demonstrated by accumulation of the protein CHOP, as well as autophagy, as demonstrated by accumulation of LC3-II proteins. Our data suggest that recruitment of both ubiquitinated proteins and LC3-II by p62 directs ubiquitinated proteins, including I-κBα, to the autophagosome. Degradation of I-κBα results in increased NF-κB nuclear translocation and transcription activity. Since bortezomib treatment promoted I-κBα phosphorylation, ubiquitination and degradation, this suggests that the route of I-κBα degradation was not via the ubiquitin-proteasome degradation system. The autophagy inhibitor chloroquine (CQ significantly inhibited bortezomib-induced I-κBα degradation, increased complex formation with NF-κB and reduced NF-κB nuclear translocation and DNA binding activity. Importantly, the combination of proteasome and autophagy inhibitors showed synergy in killing DLBCL cells. In summary, bortezomib-induced autophagy confers relative DLBCL cell drug resistance by eliminating I-κBα. Inhibition of both autophagy and the proteasome has great potential to kill apoptosis-resistant lymphoma cells.

  2. The roles of the pfcrt 76T and pfmdr1 86Y mutations, immunity and the initial level of parasitaemia, in predicting the outcome of chloroquine treatment in two areas with different transmission intensities

    DEFF Research Database (Denmark)

    Khalil, I F; Alifrangis, M; Tarimo, D S;

    2005-01-01

    , and the ability to clear P. falciparum parasites carrying the key chloroquine-resistance (CQR) mutations, pfcrt 76T and pfmdr1 86Y. Identical CQ-efficacy trials were performed in 51 young children (aged <5 years) from Kibaha, in north-western Tanzania, and 44 patients (aged 3-57 years) from Darawish......, in eastern Sudan. In both areas, all the CQ-treatment failures had infections with the 76T and 86Y alleles before treatment. Although the presence of these two alleles was significantly associated with treatment failure in Sudan (P=0.001), the corresponding association in Tanzania did not reach......-values of 0.05 in Tanzania and 0.01 in Sudan) and with age-- the best surrogate for protective immunity in endemic areas (with P-values of 0.02 in Tanzania and 0.001 in Sudan). These results confirm previous observations that indicated that the 76T and 86Y alleles play a role in the mechanism of CQR...

  3. Oxygen-reducing catalyst layer

    Science.gov (United States)

    O'Brien, Dennis P.; Schmoeckel, Alison K.; Vernstrom, George D.; Atanasoski, Radoslav; Wood, Thomas E.; Yang, Ruizhi; Easton, E. Bradley; Dahn, Jeffrey R.; O'Neill, David G.

    2011-03-22

    An oxygen-reducing catalyst layer, and a method of making the oxygen-reducing catalyst layer, where the oxygen-reducing catalyst layer includes a catalytic material film disposed on a substrate with the use of physical vapor deposition and thermal treatment. The catalytic material film includes a transition metal that is substantially free of platinum. At least one of the physical vapor deposition and the thermal treatment is performed in a processing environment comprising a nitrogen-containing gas.

  4. THz spectrum of reduced glutathione

    Institute of Scientific and Technical Information of China (English)

    WANG; Weining; YAN; Haitao; YUE; Weiwei; ZHAO; Guozhong; Z

    2005-01-01

    The optical characteristics of reduced glutathione molecules between 0.2 THz and 2.4 THz have been investigated by THz time-domain spectroscopy (THz-TDS). The absorption characteristics and optical parameters of the reduced glutathione purged with Nitrogen at room temperature were obtained experimentally. The measured results were fitted well with the theoretical results computed by using Density Functional Theory (DFT) in far-infrared range. Also the conformation of the reduced glutathione molecule was simulated by Gaussian 03. This work has demonstrated significantly that THz-TDS spectroscopy can further be used to study other biological molecules in biological and biomedical engineering.

  5. Reduced-Dimension Multiuser Detection

    CERN Document Server

    Xie, Yao; Goldsmith, Andrea

    2011-01-01

    We explore several reduced-dimension multiuser detection (RD-MUD) structures that significantly decrease the number of required correlation branches at the receiver front-end, while still achieving performance similar to that of the conventional matched-filter (MF) bank. RD-MUD exploits the fact that the number of active users is typically small relative to the total number of users in the system and relies on ideas of analog compressed sensing to reduce the number of correlators. We first develop a general framework for both linear and nonlinear RD-MUD detectors. We then present theoretical performance analysis for two specific detectors: the linear reduced-dimension decorrelating (RDD) detector, which combines subspace projection and thresholding to determine active users and sign detection for data recovery, and the nonlinear reduced-dimension decision-feedback (RDDF) detector, which combines decision-feedback orthogonal matching pursuit for active user detection and sign detection for data recovery. The t...

  6. In vitro evaluation of quinidine sensitivity in brazilian Plasmodium falciparum isolates: comparative analysis to quinine and chloroquine Avaliação da sensibilidade in vitro à quinidina em isolados brasileiros de Plasmodium falciparum: análise comparativa à quinina e à cloroquina

    Directory of Open Access Journals (Sweden)

    Carla M. S. MENEZES

    2001-08-01

    Full Text Available Falciparum malaria represents a serious and an increasing world public health problem due to the acquired parasite's resistance to the most available drugs. In some endemic areas, quinidine, a diastereoisomer of the antimalarial quinine, has been employed for replacing the latter. In order to evaluate the use of quinidine as an alternative to the increasing loss of quinine effectiveness in Brazilian P. falciparum strains, as has been observed in the Amazon area, we have assayed quinidine, quinine and chloroquine. The in vitro microtechnique was employed. All isolates showed to be highly resistant to chloroquine. Resistance to quinine was not noted although high MIC (minimal inhibitory concentration values have been observed. These data corroborate the decreasing sensitivity to quinine in strains from Brazil. Quinidine showed IC50 from 0.053 to 4.577 mumol/L of blood while IC50 from 0.053 to 8.132 mumol/L of blood was estimated for quinine. Moreover, clearance of the parasitemia was observed in concentrations lower than that used for quinidine in antiarrhythmic therapy, confirming our previous data. The results were similar to African isolate.Malária falciparum representa grave e crescente problema de saúde pública mundial, dada a resistência do parasito à maioria dos fármacos disponíveis. Em algumas áreas endêmicas, a quinidina, diastereoisômero do antimalárico quinina, vem sendo empregada em substituição a este último. Com o objetivo de avaliar o emprego da quinidina como alternativa à perda crescente de sensibilidade de cepas brasileiras de P. falciparum à quinina, como o observado na região Amazônica, realizamos ensaio comparativo entre quinidina, quinina e cloroquina. A técnica in vitro do microteste de sensibilidade foi utilizada. Todos os isolados mostraram-se altamente resistentes à cloroquina. Resistência à quinina não foi observada, embora altos valores de CMI (concentração mínima inibitória tenham sido

  7. Creation of cloned strains of chloroquine-resistant Plasmodium falciparum from Yunnan, China with resistance to dihydroartemisinin%云南省抗氯喹恶性疟原虫双氢青蒿素抗性株体外培育与单克隆品系的建立

    Institute of Scientific and Technical Information of China (English)

    杨亚明; 李雪平; 张苍林; 李奔福; 刘慧; 李丽

    2013-01-01

    目的 建立云南省恶性疟原虫抗双氢青蒿素的单克隆品系,为开展恶性疟原虫对青蒿素类的抗药性研究奠定基础. 方法 体外长期连续培养恶性疟原虫,采用体外间断双氢青蒿素药物刺激法对恶性疟原虫株进行抗药性培育,待达到一定抗药性后采用有限稀释法对虫株进行克隆,采用体外微量法测定克隆虫株对双氢青蒿素、青蒿素、氯喹的敏感性,并对其生物学特性进行鉴定. 结果 获得2个云南氯喹抗性恶性疟原虫对双氢青蒿素抗性的单克隆品系C10和H6,IC50值分别为39.01 nmol/L和26.91 nmol/L. 结论 经过8次体外间断药物刺激和筛选,获得2株恶性疟双氢青蒿素抗性单克隆品系,其药物耐受性水平与现场抗性株接近.%Objectives To establish monoclonal strains of Plasmodium falciparum from Yunnan Province with resistance to dihydroartemisinin and to lay the foundation for study of the resistance of P.falciparum to artemisinin-based drugs.Methods Strains of P.falciparum were cultured via long-term continuous in vitro culturing.Strains were intermittently challenged with dihydroartemisinin in vitro.After the strains developed a certain level of resistance to dihydroartemisinin according to a microtest assay,they were cloned using a limited dilution.Biological characteristics of sensitivity to dihydroartemisinin,artemisinin,and chloroquine in vitro were identified.Results Two monoclonal strains of dihydroartemisinin-resistant P.falciparum were obtained from chloroquine resistant P.falciparum originating in Yunnan.The IC50 of the C10 cloned strain was 39.01nmol/L and the IC50 of the H6 cloned strain was 26.91 nmol/L.Conclusion Two monoclonal strains of dihydroartemisinin-resistant P.falciparum were obtained after the parasites were intermittently challenged with 8 rounds of dihydroartemisinin in vitro.These strains had a level of drug resistance close to that of resistant strains from Yunnan.

  8. Determining Reduced Order Models for Optimal Stochastic Reduced Order Models

    Energy Technology Data Exchange (ETDEWEB)

    Bonney, Matthew S. [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Brake, Matthew R.W. [Sandia National Lab. (SNL-CA), Livermore, CA (United States)

    2015-08-01

    The use of parameterized reduced order models(PROMs) within the stochastic reduced order model (SROM) framework is a logical progression for both methods. In this report, five different parameterized reduced order models are selected and critiqued against the other models along with truth model for the example of the Brake-Reuss beam. The models are: a Taylor series using finite difference, a proper orthogonal decomposition of the the output, a Craig-Bampton representation of the model, a method that uses Hyper-Dual numbers to determine the sensitivities, and a Meta-Model method that uses the Hyper-Dual results and constructs a polynomial curve to better represent the output data. The methods are compared against a parameter sweep and a distribution propagation where the first four statistical moments are used as a comparison. Each method produces very accurate results with the Craig-Bampton reduction having the least accurate results. The models are also compared based on time requirements for the evaluation of each model where the Meta- Model requires the least amount of time for computation by a significant amount. Each of the five models provided accurate results in a reasonable time frame. The determination of which model to use is dependent on the availability of the high-fidelity model and how many evaluations can be performed. Analysis of the output distribution is examined by using a large Monte-Carlo simulation along with a reduced simulation using Latin Hypercube and the stochastic reduced order model sampling technique. Both techniques produced accurate results. The stochastic reduced order modeling technique produced less error when compared to an exhaustive sampling for the majority of methods.

  9. Municipal actions to reduce mercury

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-03-15

    This paper presented proper management practices for products containing mercury. The measures can help reduce mercury releases, occupational exposure and mercury spills, thereby preventing impacts on human health and the environment. Despite mercury's toxic nature, many common products that contain mercury are commercially available. These include thermostats, thermometers, fluorescent lamps, pressure measuring devices, electrical switches and relays, and dental amalgam. Mercury emissions are also associated with base metal smelting, waste incineration and coal-fired power generation. Mercury in the environment is a global issue, because it can travel in the atmosphere on wind currents. The actions taken by municipalities to address the issue include reducing or eliminating mercury releases from internal municipal operations and sources within the community. This document provided guidance on how to develop a Municipal Mercury Elimination Policy and Plan that will help reduce mercury releases. It presented information and case studies that will help municipalities manage mercury-containing products found in municipal buildings and street lighting. Information on sources of mercury from within the community was presented along with case studies that can help municipalities determine where community action is needed to reduce mercury releases. The 5 modules of this document were intended to help municipalities identify priorities, timelines and budget requirements for mercury initiatives. It was emphasized that municipalities that adopt a Municipal Mercury Elimination Policy and Plan formally commit to reducing and eliminating mercury from the environment. tabs., figs.

  10. Reduce air, reduce compliance cost new patented spray booth technology

    Energy Technology Data Exchange (ETDEWEB)

    McGinnis, F. [JBI, Inc., Osseo, WI (United States)

    1997-12-31

    A New Paint Spray Booth System that dramatically reduces air volumes normally required for capturing and controlling paint overspray that contains either Volatile Organic Compounds (VOC) or Hazardous Air Pollutants (HAP), or both. In turn, a substantial reduction in capital equipment expenditures for air abatement systems and air make-up heaters as well as related annual operating expenses is realized.

  11. Power and reduced temporal discounting.

    Science.gov (United States)

    Joshi, Priyanka D; Fast, Nathanael J

    2013-04-01

    Decision makers generally feel disconnected from their future selves, an experience that leads them to prefer smaller immediate gains to larger future gains. This pervasive tendency is known as temporal discounting, and researchers across disciplines are interested in understanding how to overcome it. Following recent advances in the power literature, we suggest that the experience of power enhances one's connection with the future self, which in turn results in reduced temporal discounting. In Study 1, we found that participants assigned to high-power roles were less likely than participants assigned to low-power roles to display temporal discounting. In Studies 2 and 3, priming power reduced temporal discounting in monetary and nonmonetary tasks, and, further, connection with the future self mediated the relation between power and reduced discounting. In Study 4, experiencing a general sense of power in the workplace predicted actual lifetime savings. These results have important implications for future research.

  12. Reducing ammonia emissions in Europe

    DEFF Research Database (Denmark)

    Jacobsen, Brian H.

    2011-01-01

    The NEC directive has set targets for the 2010 ammonia emissions from a number of European countries. The target will be reached by most EU-countries and the total emission for EU-27 has been reduced by 22% from 1990 to 2007. Denmark is one of the countries with the largest reductions since 1990...... to the high expectations at the outset. Despite this, the paper concludes that Denmark is likely to reduce emission by 50% from 1990 to 2020 and reach the likely 2020 NEC ceiling....

  13. National compacts to reduce deforestation

    Energy Technology Data Exchange (ETDEWEB)

    Santilli, M. [Instituto Socioambiental ISA., Brasilia DF (Brazil); Moutinho, P.; Nepstad, D. [Instituto de Pesquisa Ambiental da Amazonia IPAM, Belem (Brazil)

    2005-07-01

    Finding ways for developing countries with tropical forests to participate more effectively in international efforts to reduce greenhouse gas (GHG) emissions has become central to the success of any future international agreement. The most obvious means would be the reduction of tropical deforestation and the emissions associated with it. Unless tropical deforestation is reduced it will not be possible to avoid 'dangerous anthropogenic interference' in the planet's climate. In this chapter the necessary conditions for these countries to use reduced deforestation, in the context of 'compensated reduction of deforestation', as an internationally recognized, valid form of mitigation of global climate change and, in return, receive compensation for demonstrated reductions. The proposal for compensated reduction suggests that countries that reduce their emissions from tropical deforestation during a Kyoto Protocol commitment period, in relation to an agreed baseline in accordance with historical deforestation rates, be remunerated with credits equivalent to the volume of emissions avoided, tradable in subsequent commitment periods. As we know, under the current terms of the Kyoto Protocol, covering the first commitment period, there are no means to offer incentives for reducing deforestation, which are a recognized factor in global emissions (25%). Eligible forestry projects in the Clean Development Mechanism (CDM) include only carbon sequestration. Since tropical deforestation is a problem occurring in non-Annex 1 developing countries, and is associated with development strategies historically linked to global markets, international instruments to encourage reduction of deforestation emissions should consider the objective conditions of these countries in a manner consistent with the principle of mutual, but differentiated responsibilities. The compensated reduction proposal emerges in this context: more effective participation of these

  14. Reducing cement's CO2 footprint

    Science.gov (United States)

    van Oss, Hendrik G.

    2011-01-01

    The manufacturing process for Portland cement causes high levels of greenhouse gas emissions. However, environmental impacts can be reduced by using more energy-efficient kilns and replacing fossil energy with alternative fuels. Although carbon capture and new cements with less CO2 emission are still in the experimental phase, all these innovations can help develop a cleaner cement industry.

  15. Reducing Smoking among Pregnant Adolescents.

    Science.gov (United States)

    Duffy, Joanne; Coates, Thomas J.

    1989-01-01

    Describes psychosocial intervention designed to reduce smoking in a group of pregnant teenagers. Five modules are presented, each being designed to heighten awareness of the issue; provide motivational messages; enhance the adolescent's social skills; and teach specific smoking-cessation skills. (Author/NB)

  16. Reduced False Memory after Sleep

    Science.gov (United States)

    Fenn, Kimberly M.; Gallo, David A.; Margoliash, Daniel; Roediger, Henry L., III; Nusbaum, Howard C.

    2009-01-01

    Several studies have shown that sleep contributes to the successful maintenance of previously encoded information. This research has focused exclusively on memory for studied events, as opposed to false memories. Here we report three experiments showing that sleep reduces false memories in the Deese-Roediger-McDermott (DRM) memory illusion. False…

  17. Solitons reduced from Heterotic fivebranes

    CERN Document Server

    La, H S

    1992-01-01

    In view of the expectation that the solitonic sector of the lower dimensional world may be originated from the solitonic sector of string theory, various solitonic solutions are reduced from the heterotic fivebrane solutions in the ten-dimensional heterotic string theory. These solitons in principle can appear after proper compactifications, {\\it e.g.} toroidal compactifications.

  18. Does Microfinance Reduce Income Inequality?

    NARCIS (Netherlands)

    Hermes, Niels

    2014-01-01

    This study addresses the question whether participation of the poor in microfinance contributes to reducing a country’s level of income inequality. Using data from 70 developing countries, we show that higher levels of microfinance participation are indeed associated with a reduction of the income g

  19. Reducing Poverty through Preschool Interventions

    Science.gov (United States)

    Duncan, Greg J.; Ludwig, Jens; Magnuson, Katherine A.

    2007-01-01

    Greg Duncan, Jens Ludwig, and Katherine Magnuson explain how providing high-quality care to disadvantaged preschool children can help reduce poverty. In early childhood, they note, children's cognitive and socioemotional skills develop rapidly and are sensitive to "inputs" from parents, home learning environments, child care settings, and the…

  20. A reduced-turbulence, reduced-entrainment electrostatic precipitator

    OpenAIRE

    Bahner, Mark A.

    1990-01-01

    This thesis describes testing of an electrostatic precipitator that has a portion of the main precipitator flow drawn through a porous (fabric) collecting surface. Tests investigated effects of flow through the collecting surface (side flow) on precipitator turbulence and particulate removal efficiency. Particulate removal tests were conducted at both ambient temperature and boiler slipstream conditions. Side flow was shown to reduce turbulence in the boundary layers of the collecting plat...

  1. Reduced modified Chaplygin gas cosmology

    Science.gov (United States)

    Lu, Jianbo; Geng, Danhua; Xu, Lixin; Wu, Yabo; Liu, Molin

    2015-02-01

    In this paper, we study cosmologies containing the reduced modified Chaplygin gas (RMCG) fluid which is reduced from the modified Chaplygin gas p = Aρ - Bρ -α for the value of α = -1 /2. In this special case, dark cosmological models can be realized for different values of model parameter A. We investigate the viabilities of these dark cosmological models by discussing the evolutions of cosmological quantities and using the currently available cosmic observations. It is shown that the special RMCG model ( A = 0 or A = 1) which unifies the dark matter and dark energy should be abandoned. For A = 1 /3, RMCG which unifies the dark energy and dark radiation is the favorite model according to the objective Akaike information criteria. In the case of A , RMCG can achieve the features of the dynamical quintessence and phantom models, where the evolution of the universe is not sensitive to the variation of model parameters.

  2. Ferroelectric capacitor with reduced imprint

    Energy Technology Data Exchange (ETDEWEB)

    Evans, Jr., Joseph T. (13609 Verbena Pl., NE., Albuquerque, NM 87112); Warren, William L. (7716 Wm. Moyers Ave., NE., Albuquerque, NM 87122); Tuttle, Bruce A. (12808 Lillian Pl., NE., Albuquerque, NM 87122); Dimos, Duane B. (6105 Innsbrook Ct., NE., Albuquerque, NM 87111); Pike, Gordon E. (1609 Cedar Ridge, NE., Albuquerque, NM 87112)

    1997-01-01

    An improved ferroelectric capacitor exhibiting reduced imprint effects in comparison to prior art capacitors. A capacitor according to the present invention includes top and bottom electrodes and a ferroelectric layer sandwiched between the top and bottom electrodes, the ferroelectric layer comprising a perovskite structure of the chemical composition ABO.sub.3 wherein the B-site comprises first and second elements and a dopant element that has an oxidation state greater than +4. The concentration of the dopant is sufficient to reduce shifts in the coercive voltage of the capacitor with time. In the preferred embodiment of the present invention, the ferroelectric element comprises Pb in the A-site, and the first and second elements are Zr and Ti, respectively. The preferred dopant is chosen from the group consisting of Niobium, Tantalum, and Tungsten. In the preferred embodiment of the present invention, the dopant occupies between 1 and 8% of the B-sites.

  3. Medical waste: reducing its generation.

    Science.gov (United States)

    Belkin, N L

    1993-01-01

    1. Materials that can be recycled have yet to be proven to be a more cost-effective means of reducing medical waste. The literature indicates that the efficacy of reusable textiles is at least equal to that of some disposables--and reusable items reduce the generation of blood-contaminated waste. 2. The perioperative nursing community should consider replacing single-use items with materials intended for multiple uses. 3. "Source reduction" entails the replacement of single-use items with reusable items. Successful source-reduction programs require changes in individual and collective behavior patterns. 4. Recycling of materials renders them suitable for another use in a product similar to that in which they were originally used. On the other hand, reprocessing is an all-descriptive term of what must be done to an item to render it suitable for another identical use.

  4. Breastfeeding reduces postpartum weight retention

    DEFF Research Database (Denmark)

    Baker, Jennifer Lyn; Gamborg, Michael; Heitmann, Berit L;

    2008-01-01

    BACKGROUND: Weight gained during pregnancy and not lost postpartum may contribute to obesity in women of childbearing age. OBJECTIVE: We aimed to determine whether breastfeeding reduces postpartum weight retention (PPWR) in a population among which full breastfeeding is common and breastfeeding...... duration is long. DESIGN: We selected women from the Danish National Birth Cohort who ever breastfed (>98%), and we conducted the interviews at 6 (n = 36 030) and 18 (n = 26 846) mo postpartum. We used regression analyses to investigate whether breastfeeding (scored to account for duration and intensity......) reduced PPWR at 6 and 18 mo after adjustment for maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG). RESULTS: GWG was positively (P Breastfeeding was negatively associated with PPWR in all women but those...

  5. Alcohol reduces aversion to ambiguity

    Directory of Open Access Journals (Sweden)

    Tadeusz eTyszka

    2015-01-01

    Full Text Available Several years ago, Cohen, Dearnaley, and Hansel [1] demonstrated that under the influence of alcohol drivers became more risk prone, although their risk perception remained unchanged. Research shows that ambiguity aversion is to some extent positively correlated with risk aversion, though not very highly [2]. The question addressed by the present research is whether alcohol reduces ambiguity aversion. Our research was conducted in a natural setting (a restaurant bar, where customers with differing levels of alcohol intoxication were offered a choice between a risky and an ambiguous lottery. We found that alcohol reduced ambiguity aversion and that the effect occurred in men but not women. We interpret these findings in terms of the risk-as-value hypothesis, according to which, people in Western culture tend to value risk, and suggest that alcohol consumption triggers adherence to socially and culturally valued patterns of conduct different for men and women.

  6. Correlated Electrons in Reduced Dimensions

    Energy Technology Data Exchange (ETDEWEB)

    Bonesteel, Nicholas E [Florida State Univ., Tallahassee, FL (United States)

    2015-01-31

    This report summarizes the work accomplished under the support of US DOE grant # DE-FG02-97ER45639, "Correlated Electrons in Reduced Dimensions." The underlying hypothesis of the research supported by this grant has been that studying the unique behavior of correlated electrons in reduced dimensions can lead to new ways of understanding how matter can order and how it can potentially be used. The systems under study have included i) fractional quantum Hall matter, which is realized when electrons are confined to two-dimensions and placed in a strong magnetic field at low temperature, ii) one-dimensional chains of spins and exotic quasiparticle excitations of topologically ordered matter, and iii) electrons confined in effectively ``zero-dimensional" semiconductor quantum dots.

  7. Reduced Deforestation and Economic Growth

    OpenAIRE

    Patrick Doupe

    2014-01-01

    The clearing of forests for agricultural land and other marketable purposes is a well-trodden path of economic development. With these private benefits from deforestation come external costs: emissions from deforestation currently account for 12 per cent of global carbon emissions. A widespread intervention in reducing emissions from deforestation will affect the paths of agricultural expansion and economic growth of lower income nations. To investigate these processes, this paper presents a ...

  8. Numbers for reducible cubic scrolls

    Directory of Open Access Journals (Sweden)

    Israel Vainsencher

    2004-12-01

    Full Text Available We show how to compute the number of reducible cubic scrolls of codimension 2 in (math blackboard symbol Pn incident to the appropriate number of linear spaces.Mostramos como calcular o número de rolos cúbicos redutíveis de codimensão 2 em (math blackboard symbol Pn incidentes a espaços lineares apropriados.

  9. Combined Reduced-Rank Transform

    Directory of Open Access Journals (Sweden)

    Anatoli Torokhti

    2006-04-01

    Full Text Available We propose and justify a new approach to constructing optimal nonlinear transforms of random vectors. We show that the proposed transform improves such characteristics of {rank-reduced} transforms as compression ratio, accuracy of decompression and reduces required computational work. The proposed transform ${mathcal T}_p$ is presented in the form of a sum with $p$ terms where each term is interpreted as a particular rank-reduced transform. Moreover, terms in ${mathcal T}_p$ are represented as a combination of three operations ${mathcal F}_k$, ${mathcal Q}_k$ and ${oldsymbol{varphi}}_k$ with $k=1,ldots,p$. The prime idea is to determine ${mathcal F}_k$ separately, for each $k=1,ldots,p$, from an associated rank-constrained minimization problem similar to that used in the Karhunen--Lo`{e}ve transform. The operations ${mathcal Q}_k$ and ${oldsymbol{varphi}}_k$ are auxiliary for f/inding ${mathcal F}_k$. The contribution of each term in ${mathcal T}_p$ improves the entire transform performance. A corresponding unconstrained nonlinear optimal transform is also considered. Such a transform is important in its own right because it is treated as an optimal filter without signal compression. A rigorous analysis of errors associated with the proposed transforms is given.

  10. Reducing consumption through communal living

    Energy Technology Data Exchange (ETDEWEB)

    Herring, Horace [The Open Univ., Milton Keynes (United Kingdom). Energy and Environment Research Unit

    2003-07-01

    This paper examines ways consumers and communities can voluntarily adopt a low consumption (or low carbon) lifestyle, often termed 'voluntary simplicity' or a policy of 'sufficiency'. There is an increasing academic literature within Europe in the last five years on the whole question of 'sustainable consumption', and the relationship between income levels and consumption particularly at the household. This debate has moved beyond 'green consumerism' to look at building 'new concepts of prosperity' through local community actions, or reducing working time to allow more time for the creation of social capital. The paper will concentrate on one aspect of the quest for sustainable communities, the relevance of communal living to reducing consumption through examining energy consumption (both direct and indirect) in one such community in the UK. The results from this preliminary study reveal that it is not the sharing of resources that reduces consumption but the mutual reinforcement of attitudes towards a low consumption lifestyle. Thus it is the creation of social capital in a community that is its key to its ecological lifestyle.

  11. Does Income Inequality Reduce Growth? Does Income Inequality Reduce Growth?

    Directory of Open Access Journals (Sweden)

    Pablo Serra

    1993-03-01

    Full Text Available This paper examines the effects of inequality on the rate of growth of an economy. We assume that it is easier for an individual to achieve a given level of human capiral the higher society's average level of human capiral. Agents with above average human capital find it relatively more costly to acquire additional human capital, while agents with below average human capital find it relatively cheaper to acquire additional human capital. The existence of such an externality implies that even when where is no income inequality agents will behave inefficiently. In order to achieve the optimal growth rate, a lump sum tax must be combined with a subsidy to investment in education. When incomes are heterogenous, we show that income convergence is attained in the long run. We also show that the effect of inequality on the growth rate of an economy depends on the functional form of the externality. When the externality junction is concave, income dispersion reduces the rate of growth. On the other hand, when the externality function is convex, the effect is ambiguous. Does Income Inequality Reduce Growth?

  12. Welfare-Reducing Trade Liberalization

    DEFF Research Database (Denmark)

    Schröder, Philipp J.H.; Jørgensen, Jan G.

    Recent literature on the workhorse model of intra-industry trade has explored heterogeneous cost structures at the firm level. These approaches have proven to add realism and predictive power. This note shows, however, that this added realism also implies that there may exist a positive bilateral...... tariff that maximizes national and world welfare. Applying one of the simplest specifications possible, namely a symmetric two-country intra-industry trade model with fixed export costs that are heterogeneous across firms, we find that the reciprocal reduction of small tariffs reduces welfare. We explore...

  13. On nonlinear reduced order modeling

    International Nuclear Information System (INIS)

    When applied to a model that receives n input parameters and predicts m output responses, a reduced order model estimates the variations in the m outputs of the original model resulting from variations in its n inputs. While direct execution of the forward model could provide these variations, reduced order modeling plays an indispensable role for most real-world complex models. This follows because the solutions of complex models are expensive in terms of required computational overhead, thus rendering their repeated execution computationally infeasible. To overcome this problem, reduced order modeling determines a relationship (often referred to as a surrogate model) between the input and output variations that is much cheaper to evaluate than the original model. While it is desirable to seek highly accurate surrogates, the computational overhead becomes quickly intractable especially for high dimensional model, n ≫ 10. In this manuscript, we demonstrate a novel reduced order modeling method for building a surrogate model that employs only 'local first-order' derivatives and a new tensor-free expansion to efficiently identify all the important features of the original model to reach a predetermined level of accuracy. This is achieved via a hybrid approach in which local first-order derivatives (i.e., gradient) of a pseudo response (a pseudo response represents a random linear combination of original model’s responses) are randomly sampled utilizing a tensor-free expansion around some reference point, with the resulting gradient information aggregated in a subspace (denoted by the active subspace) of dimension much less than the dimension of the input parameters space. The active subspace is then sampled employing the state-of-the-art techniques for global sampling methods. The proposed method hybridizes the use of global sampling methods for uncertainty quantification and local variational methods for sensitivity analysis. In a similar manner to

  14. Challenging and Reducing Cultural Stereotypes

    Institute of Scientific and Technical Information of China (English)

    黄鸣

    2011-01-01

    Abstract:Anyplace where differences are found leaves room for stereotypes.Each of us hears or makes stereotypical comments every day,and although sometimes it is necessary to make stereotypes in foreign language teaching and learning,we should always be aware of the negative effects of stereotyping people from other cultures when we use them to interpret behavior.This paper defines stereotypes,discusses how they impede communication and then focuses on some ways to challenge and reduce stereotypes in cross-cultural communication.

  15. Welfare-Reducing Trade Liberalization

    DEFF Research Database (Denmark)

    Schröder, Philipp J.H.; Jørgensen, Jan G.

    Recent literature on the workhorse model of intra-industry trade has explored heterogeneous cost structures at the firm level. These approaches have proven to add realism and predictive power. This paper shows, however, that this added realism also implies that there may exist a positive bilateral...... tariff that maximizes national and world welfare. Applying one of the simplest specifications possible, namely a symmetric two-country intra-industry trade model with fixed export costs that are heterogeneous across firms, we find that the reciprocal reduction of small tariffs reduces welfare....

  16. FIREhose: Reducing Data from FIRE

    Science.gov (United States)

    Fica, Haley Diane; Lambrides, Erini; Faherty, Jackie; Cruz, Kelle L.; BDNYC

    2016-01-01

    Brown dwarfs are stellar objects that do not have enough mass to ignite hydrogen fusion in their core. Their mass is between 0.08 solar masses and the mass of our sun. Brown dwarfs are very bright in the near-infrared wavelength band (0.8- 2.5 microns). We reduced data from the Folded-port InfraRed Echellette (FIRE) instrument on the Magellan Telescope at the Las Campanas Observatory. FIRE is a medium-resolution echelle spectrometer, whose data reduction results in a spectrum of a star. When reducing FIRE data, it is important to account for inconsistencies in the data, such as bad pixels, cosmic rays, and the effects of our atmosphere. Using the FIREhose pipeline, these inconsistencies can be accounted for and corrected using a A0 telluric with a known spectrum. After telluric correcting, the data reduction results in a primed spectrum for an object, which can then be used to determine an object's physical properties, such as atmospheric composition, radial velocity, effective temperature and surface gravity.

  17. Soldering Tested in Reduced Gravity

    Science.gov (United States)

    Struk, Peter M.; Pettegrew, Richard D.; Watson, J. Kevin; Down, Robert S.; Haylett, Daniel R.

    2005-01-01

    Whether used occasionally for contingency repair or routinely in nominal repair operations, soldering will become increasingly important to the success of future long-duration human space missions. As a result, it will be critical to have a thorough understanding of the service characteristics of solder joints produced in reduced-gravity environments. The National Center for Space Exploration Research (via the Research for Design program), the NASA Glenn Research Center, and the NASA Johnson Space Center are conducting an experimental program to explore the influence of reduced gravity environments on the soldering process. Solder joint characteristics that are being considered include solder fillet geometry, porosity, and microstructural features. Both through-hole (see the drawing and image on the preceding figure) and surface-mounted devices are being investigated. This effort (the low-gravity portion being conducted on NASA s KC-135 research aircraft) uses the soldering hardware currently available on the International Space Station. The experiment involves manual soldering by a contingent of test operators, including both highly skilled technicians and less skilled individuals to provide a skill mix that might be encountered in space mission crews. The experiment uses both flux-cored solder and solid-core solder with an externally applied flux. Other experimental parameters include the type of flux, gravitational level (nominally zero,

  18. Reduced pallidal output causes dystonia

    Directory of Open Access Journals (Sweden)

    Atsushi eNambu

    2011-11-01

    Full Text Available Dystonia is a neurological disorder characterized by sustained or repetitive involuntary muscle contractions and abnormal postures. In the present article, we will introduce our recent electrophysiological studies in hyperkinetic transgenic mice generated as a model of DYT1 dystonia and in a human cervical dystonia patient, and discuss the pathophysiology of dystonia on the basis of these electrophysiological findings. Recording of neuronal activity in the awake state of DYT1 dystonia model mice revealed reduced spontaneous activity with bursts and pauses in both internal (GPi and external (GPe segments of the globus pallidus. Electrical stimulation of the primary motor cortex evoked responses composed of excitation and subsequent long-lasting inhibition, the latter of which was never observed in normal mice. In addition, somatotopic arrangements were disorganized in the GPi and GPe of dystonia model mice. In a human cervical dystonia patient, electrical stimulation of the primary motor cortex evoked similar long-lasting inhibition in the GPi and GPe. Thus, reduced GPi output may cause increased thalamic and cortical activity, resulting in the involuntary movements observed in dystonia.

  19. Reduced discretization error in HZETRN

    Science.gov (United States)

    Slaba, Tony C.; Blattnig, Steve R.; Tweed, John

    2013-02-01

    The deterministic particle transport code HZETRN is an efficient analysis tool for studying the effects of space radiation on humans, electronics, and shielding materials. In a previous work, numerical methods in the code were reviewed, and new methods were developed that further improved efficiency and reduced overall discretization error. It was also shown that the remaining discretization error could be attributed to low energy light ions (A astronaut radiation exposure. In this work, modifications to the light particle transport formalism are presented that accurately resolve the spectrum of low energy light ion target fragments. The modified formalism is shown to significantly reduce overall discretization error and allows a physical approximation to be removed. For typical step-sizes and energy grids used in HZETRN, discretization errors for the revised light particle transport algorithms are shown to be less than 4% for aluminum and water shielding thicknesses as large as 100 g/cm2 exposed to both solar particle event and galactic cosmic ray environments.

  20. Moral Violations Reduce Oral Consumption.

    Science.gov (United States)

    Chan, Cindy; Van Boven, Leaf; Andrade, Eduardo B; Ariely, Dan

    2014-07-01

    Consumers frequently encounter moral violations in everyday life. They watch movies and television shows about crime and deception, hear news reports of corporate fraud and tax evasion, and hear gossip about cheaters and thieves. How does exposure to moral violations influence consumption? Because moral violations arouse disgust and because disgust is an evolutionarily important signal of contamination that should provoke a multi-modal response, we hypothesize that moral violations affect a key behavioral response to disgust: reduced oral consumption. In three experiments, compared with those in control conditions, people drank less water and chocolate milk while (a) watching a film portraying the moral violations of incest, (b) writing about moral violations of cheating or theft, and (c) listening to a report about fraud and manipulation. These findings imply that "moral disgust" influences consumption in ways similar to core disgust, and thus provide evidence for the associations between moral violations, emotions, and consumer behavior.

  1. Variational Integrators for Reduced Magnetohydrodynamics

    CERN Document Server

    Kraus, Michael; Grasso, Daniela

    2015-01-01

    Reduced magnetohydrodynamics is a simplified set of magnetohydrodynamics equations with applications to both fusion and astrophysical plasmas, possessing a noncanonical Hamiltonian structure and consequently a number of conserved functionals. We propose a new discretisation strategy for these equations based on a discrete variational principle applied to a formal Lagrangian. The resulting integrator preserves important quantities like the total energy, magnetic helicity and cross helicity exactly (up to machine precision). As the integrator is free of numerical resistivity, spurious reconnection along current sheets is absent in the ideal case. If effects of electron inertia are added, reconnection of magnetic field lines is allowed, although the resulting model still possesses a noncanonical Hamiltonian structure. After reviewing the conservation laws of the model equations, the adopted variational principle with the related conservation laws are described both at the continuous and discrete level. We verify...

  2. Reducing catalytic converter pressure loss

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-06-01

    This article examines why approximately 30--40% of total exhaust-system pressure loss occurs in the catalytic converter and what can be done to reduce pressure loss. High exhaust-system backpressure is of concern in the design of power trains for passenger cars and trucks because it penalizes fuel economy and limits peak power. Pressure losses occur due to fluid shear and turning during turbulent flow in the converter headers and in entry separation and developing laminar-flow boundary layers within the substrate flow passages. Some of the loss mechanisms are coupled. For example, losses in the inlet header are influenced by the presence of the flow resistance of a downstream substrate. Conversely, the flow maldistribution and pressure loss of the substrate(s) depend on the design of the inlet header.

  3. Does the Internet Reduce Corruption?

    DEFF Research Database (Denmark)

    Andersen, Thomas Barnebeck; Bentzen, Jeanet Sinding; Dalgaard, Carl-Johan Lars;

    2011-01-01

    We test the hypothesis that the Internet is a useful technology for controlling corruption. In order to do so, we develop a novel identification strategy for Internet diffusion. Power disruptions damage digital equipment, which increases the user cost of IT capital, and thus lowers the speed...... of Internet diffusion. A natural phenomenon causing power disruptions is lightning activity, which makes lightning a viable instrument for Internet diffusion. Using ground-based lightning detection censors as well as global satellite data, we construct lightning density data for the contiguous U.S. states...... and a large cross section of countries. Empirically, lightning density is a strong instrument for Internet diffusion and our IV estimates suggest that the emergence of the Internet has served to reduce the extent of corruption across U.S. states and across the world....

  4. Reduced domestic satellite orbit spacing

    Science.gov (United States)

    Sharp, G. L.

    The demand for services provided by communications satellites in geostationary orbit is growing, and problems arise with respect to the required increase in capacity. One approach for providing such an increase involves the employment of more satellites operating at smaller orbital spacings. The present investigation is concerned with the results of technical studies conducted by the Federal Communications Commission (FCC) to determine the feasibility of reducing orbital spacings between U.S. 'domestic fixed satellites' (domsats). Attention is given to details regarding the usable orbital arc, an adjacent satellite interference model, antenna sidelobe patterns, a single entry analysis, a 4/6 GHz aggregate analysis, results for the 4/6 GHz bands, results for the 12/14 GHz bands, data services, voice services, video reception, and high power spot beams.

  5. Periocular Recognition Using Reduced Features

    Directory of Open Access Journals (Sweden)

    Ambika D R,

    2013-08-01

    Full Text Available Biometrics is science of measuring and statistically analyzing biological data. Biometric system establishes identity of a person based on unique physical or behavioural characteristic possessed by an individual. Behavioural biometrics measures characteristics which are acquired naturally over time. Physical biometrics measures inherent physical characteristics on a n individual. Over the last few decades enormous attention is drawn towards ocular biometrics. Cues provided by ocular region have led to exploration of newer traits. Feasibility of periocular region as a useful biometric trait has been explored recently. With the promising results of preliminary examination, research towards periocular region is currently gaining lot of prominence. Researchers have analyzed various techniques of feature extraction and classification in the periocular region. The current paper investigates the effect of using Lower Central Periocular Region (LCPR for identification. The results obtained are comparable with those acquired for the entire periocular region with an advantage of reduced periocular area.

  6. Interventions to reduce school bullying.

    Science.gov (United States)

    Smith, Peter K; Ananiadou, Katerina; Cowie, Helen

    2003-10-01

    In the last 2 decades, school bullying has become a topic of public concern and research around the world. This has led to action to reduce the problem. We review interventions targeted at the school level (for example, whole school policy, classroom climate, peer support, school tribunal, and playground improvement), at the class level (for example, curriculum work), and at the individual level (for example, working with specific pupils). Effectiveness of interventions has been sporadically assessed. We review several systematically evaluated, large-scale, school-based intervention programs. Their effectiveness has varied, and we consider reasons for this. We suggest ways to improve the evaluation and comparability of studies, as well as the effectiveness of future interventions. PMID:14631879

  7. Neuromuscular Adaptations to Reduced Use

    Science.gov (United States)

    Ploutz-Snyder, Lori

    2009-01-01

    This viewgraph presentation reviews the studies done to reduce neuromuscular strength loss during unilateral lower limb suspension (ULLS). Since there are animals that undergo fairly long periods of muscular disuse without any or minimal muscular atrophy, there is an answer to that might be applicable to human in situations that require no muscular use to diminish the effects of muscular atrophy. Three sets of ULLS studies were reviewed indicated that muscle strength decreased more than the muscle mass. The study reviewed exercise countermeasures to combat the atrophy, including: ischemia maintained during Compound muscle action potential (CMAP), ischemia and low load exercise, Japanese kaatsu, and the potential for rehabilitation or situations where heavy loading is undesirable. Two forms of countermeasures to unloading have been successful, (1) high-load resistance training has maintained muscle mass and strength, and low load resistance training with blood flow restriction (LL(sub BFR)). The LL(sub BFR) has been shown to increase muscle mass and strength. There has been significant interest in Tourniquet training. An increase in Growth Hormone(GH) has been noted for LL(sub BFR) exercise. An experimental study with 16 subjects 8 of whom performed ULLS, and 8 of whom performed ULLS and LL(sub BFR) exercise three times per week during the ULLS. Charts show the results of the two groups, showing that performing LL(sub BFR) exercise during 30 days of ULLS can maintain muscle size and strength and even improve muscular endurance.

  8. The benefits of reduced morbidity

    International Nuclear Information System (INIS)

    Morbidity benefits refer to increases in utility arising from reductions in incidents of acute health impairments and from increases in the probability of developing chronic diseases. The impairments would run the gamut from a cough-day to a bed-disability-day, while the chronic diseases include classic pollution-related diseases, such as cancer, to in utero effects and learning disabilities. As with mortality benefits, there could be benefits to oneself and family and friends as well as benefits based on altruism. A major difference between the mortality and morbidity valuation literatures is that while estimates of the former are always based on risk (one is never trying to obtain values for avoiding certain death), estimates of the latter generally are not. That is, most of the theory and empirical estimates are based on models where the effect to be avoided is certain. This assumption holds reasonably well for estimating common acute effects, for example, the willingness to pay (WTP) for one less cough-day. It works less well, if at all, for chronic illness endpoints, where benefits seem to be appropriately expressed in terms of reduced risk of developing a disease or impairment

  9. Variational integrators for reduced magnetohydrodynamics

    Science.gov (United States)

    Kraus, Michael; Tassi, Emanuele; Grasso, Daniela

    2016-09-01

    Reduced magnetohydrodynamics is a simplified set of magnetohydrodynamics equations with applications to both fusion and astrophysical plasmas, possessing a noncanonical Hamiltonian structure and consequently a number of conserved functionals. We propose a new discretisation strategy for these equations based on a discrete variational principle applied to a formal Lagrangian. The resulting integrator preserves important quantities like the total energy, magnetic helicity and cross helicity exactly (up to machine precision). As the integrator is free of numerical resistivity, spurious reconnection along current sheets is absent in the ideal case. If effects of electron inertia are added, reconnection of magnetic field lines is allowed, although the resulting model still possesses a noncanonical Hamiltonian structure. After reviewing the conservation laws of the model equations, the adopted variational principle with the related conservation laws is described both at the continuous and discrete level. We verify the favourable properties of the variational integrator in particular with respect to the preservation of the invariants of the models under consideration and compare with results from the literature and those of a pseudo-spectral code.

  10. Reduced surround inhibition in musicians.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H

    2012-06-01

    To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

  11. Hamiltonian formulation of reduced magnetohydrodynamics

    International Nuclear Information System (INIS)

    Reduced magnetohydrodynamics (RMHD) has become a principal tool for understanding nonlinear processes, including disruptions, in tokamak plasmas. Although analytical studies of RMHD turbulence have been useful, the model's impressive ability to simulate tokamak fluid behavior has been revealed primarily by numerical solution. The present work describes a new analytical approach, not restricted to turbulent regimes, based on Hamiltonian field theory. It is shown that the nonlinear (ideal) RMHD system, in both its high-beta and low-beta versions, can be expressed in Hanmiltonian form. Thus a Poisson bracket, [ , ], is constructed such that each RMHD field quantitity, xi/sub i/, evolves according to xi/sub i/ = [xi/sub i/,H], where H is the total field energy. The new formulation makes RMHD accessible to the methodology of Hamiltonian mechanics; it has lead, in particular, to the recognition of new RMHD invariants and even exact, nonlinear RMHD solutions. A canonical version of the Poisson bracket, which requires the introduction of additional fields, leads to a nonlinear variational principle for time-dependent RMHD

  12. Yolk androgens reduce offspring survival.

    Science.gov (United States)

    Sockman, K W; Schwabl, H

    2000-07-22

    Females may favour some offspring over others by differential deposition of yolk hormones. In American kestrels (Falco sparverius), we found that yolks of eggs laid late in the sequence of a clutch had more testosterone (T) and androstenedione (A4) than yolks of first-laid eggs. To investigate the effects of these yolk androgens on nestling 'fitness', we injected both T and A4 into the yolks of first-laid eggs and compared their hatching time, nestling growth and nestling survival with those of first-laid eggs in which we injected vehicle as a control. Compared to controls, injection of T and A4 at a dose intended to increase their levels to those of later-laid eggs delayed hatching and reduced nestling growth and survival rates. Yolk androgen treatment of egg 1 had no effect on survival of siblings hatching from subsequently laid eggs. The adverse actions of yolk androgen treatment in the kestrel are in contrast to the favourable actions of yolk T treatment found previously in canaries (Serinus canaria). Additional studies are necessary in order to determine whether the deposition of yolk androgens is an adaptive form of parental favouritism or an adverse by-product of endocrine processes during egg formation. Despite its adaptive significance, such 'transgenerational' effects of steroid hormones may have helped to evolutionarily shape the hormonal mechanisms regulating reproduction. PMID:10983830

  13. Reducing carbon-in-ash

    Energy Technology Data Exchange (ETDEWEB)

    Nigel S. Dong [IEA Clean Coal Centre, London (United Kingdom)

    2010-05-15

    High levels of carbon-in-ash lead to reduced power plant efficiency and higher fuel costs, degrade the performance of electrostatic precipitators and increase emissions of particulates. Increased carbon levels in the fly ash can lead to problems with ash use in cement/concrete production. This report reviews current measures and technologies that can be used to prevent excessive carbon-in-ash in pulverised coal combustion (PCC) power plants. These include coal cleaning, coal fineness improvement, reduction of distribution imbalance of coal among burners, increasing coal-air mixing rates at both burner and OFA levels and optimising excess air ratios. A plasma-assisted combustion enhancement technology can help achieve better ignition and more stable flame for coals that are normally difficult to burn. Computer-based combustion optimisation using expert systems, neural network systems and coal combustion simulation is becoming an invaluable means to tackle the carbon-in-ash issue. This report also reviews the regulations in nine major coal-consuming countries, which stipulate the maximum unburnt carbon levels permitted for fly ash for use in concrete/cement production. The Loss on Ignition (LOI) parameter is used in all national standards, although it is considered inadequate and may exclude some usable fly ash from being utilised. Performance-based regulations are more appropriate and have been adopted by Canada and USA. The EU and Canada now permit the use of fly ash produced from co-combustion of coal and biomass. China and Russia allow very high LOI levels for certain fly ash but the other countries require similar LOI limits for fly ash for use in concrete. Finally, this report discusses measures and technologies for reduction of carbon-in-ash, including classification, froth flotation, triboelectrostatic separators, thermal processes and carbon surface modification. 146 refs., 19 figs., 15 tabs.

  14. Meditation Helps Reduce Hardened Arteries

    Institute of Scientific and Technical Information of China (English)

    Sue; Pleming; 林兆佩

    2000-01-01

    沉思冥想可以减少人体冠状动脉内壁的厚度、降低心脏病和中风的危险。这话听上去有点玄乎,可是,这是事实。而且,这不是崇尚气功的国人的结论,而是美国医生的实验所证实的事实。 简称为TM(由Transcendental[超然的;超验的]Meditation的首字母所组成)的方法每日进行两次,每次20分钟。同时还得使用所谓a specific sound or“mental vehicle”(精神媒介物)。其目的是:…enabled the person to experiencequieter states of thinking.其背后的原因是:…heart disease was associated withpsychological stress and that meditating could reduce this。以下一句间接告诉我们:所谓TM,并非一两句话就能交代明白: The meditation group was given five to eight hours of tuition on TM tech—niques… 美国的研究人员常运用“对比法”来作下结论。本文也不例外。 本文给我们的重要启示是:…heart disease was associated with psychologicalstress.而quieter states of thinking是强身健体之关键。

  15. Effects of Low Dose of Ketotifen and Chloroquine Combination on the Ultras tructure of Chloroquine Resistant Strain of Plasmodium Yoelii

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    1 Introduction Thewidespreaddevelopmentofchloroquineresis tant (CR)strainofmalariahasresultedinsearchingforneweffectiveanti malariadrugs[1~ 4 ] .Ananti asthmaandanti malariadrugketotifen (K)hasbeenprovedtoshowstronganti malariaactionbyPanetal[5~ 7] .FurthermoreKhadstrongerreverseeffectonP .yoelii (CR)thanVerapmil[8] .TheultrastructurestudyhasrevealedthattheeffectofK ( 10mg·kg- 1·d- 1)onchloroquine sensitive(CS)strainofP .yoeliiandK ( 4 0mg/kg·d)onP .yoelii (CR)isdifferentfromotheranti malariadrugswiththecha...

  16. Would Weaker Beer Help Reduce Alcohol's Harms?

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_160387.html Would Weaker Beer Help Reduce Alcohol's Harms? Researchers say drinkers wouldn' ... 2016 (HealthDay News) -- Lowering the alcohol content in beer and other drinks may help reduce their harmful ...

  17. Generalized Reduced Order Model Generation Project

    Data.gov (United States)

    National Aeronautics and Space Administration — M4 Engineering proposes to develop a generalized reduced order model generation method. This method will allow for creation of reduced order aeroservoelastic state...

  18. Microprocessor Protection of Power Reducing Transformers

    OpenAIRE

    F. A. Romanuk; Korolev, S. P.; M. S. Loman

    2011-01-01

    The paper contains analysis of advantages and disadvantages of existing differential protection terminals of power reducing transformers. The paper shows that there are good reasons to develop microprocessor protection of power reducing transformer which contains required functions and settings and which is based on Belarusian principles of relay protection system construction. The paper presents functional structure of microprocessor terminal of power reducing transformer which is developed. 

  19. Microprocessor Protection of Power Reducing Transformers

    Directory of Open Access Journals (Sweden)

    F. A. Romanuk

    2011-01-01

    Full Text Available The paper contains analysis of advantages and disadvantages of existing differential protection terminals of power reducing transformers. The paper shows that there are good reasons to develop microprocessor protection of power reducing transformer which contains required functions and settings and which is based on Belarusian principles of relay protection system construction. The paper presents functional structure of microprocessor terminal of power reducing transformer which is developed. 

  20. Parallel Processing of cluster by Map Reduce

    Directory of Open Access Journals (Sweden)

    Madhavi Vaidya

    2012-02-01

    Full Text Available MapReduce is a parallel programming model and an associated implementation introduced by Google. In the programming model, a user specifies the computation by two functions, Map and Reduce. The underlying MapReduce library automatically parallelizes the computation, and handles complicated issues like data distribution, load balancing and fault tolerance. Massive input, spread across many machines, need to parallelize. Moves the data, and provides scheduling, fault tolerance. The original MapReduce implementation by Google, as well as its open-source counterpart, Hadoop, is aimed for parallelizing computing in large clusters of commodity machines. Map Reduce has gained a great popularity as it gracefully and automatically achieves fault tolerance. It automatically handles the gathering of results across the multiple nodes and returns a single result or set. This paper gives an overview of MapReduce programming model and its applications. The author has described here the workflow of MapReduce process. Some important issues, like fault tolerance, arestudied in more detail. Even the illustration of working of Map Reduce is given. The data locality issue in heterogeneous environments can noticeably reduce the Map Reduce performance. In this paper, the author has addressed the illustration of data across nodes in a way that each node has a balanced data processing load stored in a parallel manner. Given a data intensive application running on a Hadoop Map Reduce cluster, the auhor has exemplified how data placement is done in Hadoop architecture and the role of Map Reduce in the Hadoop Architecture. The amount of data stored in each node to achieve improved data-processing performance is explained here.

  1. Interpretation of the reduced density gradient

    OpenAIRE

    Boto, Roberto A.; Contreras-García, Julia; Tierny, Julien; Piquemal, Jean-Philip

    2015-01-01

    An interpretation of the reduced density gradient in terms of the bosonic kinetic energy density is presented. Contrary to other bonding indicators based on the kinetic energy density such as the localised orbital locator (LOL) or the electron localization function (ELF), the reduced density gradient is not only able to identify covalent bondings, but also ionic and non-covalent interactions. This study reveals that the critical points of the reduced density gradient are closely connected wit...

  2. Reducing energy costs in nursing homes

    Energy Technology Data Exchange (ETDEWEB)

    1981-01-01

    The handbook presents ideas and techniques for energy conservation in nursing homes. Case studies were developed of nursing homes located in different parts of the US. The typical nursing home assessed was proprietary, of intermediate-care level, medicaid-certified, and had less than 200 beds. Specific energy conservation measures were analyzed to determine the energy and dollar savings that could be realized. These include reducing heat loss through the building shell; reducing hot water costs; recovering the heat generated by dryers; reducing lighting costs; reducing heating and cooling costs, and analyzing fuels and fuel rates. A case for converting electric clothes dryers to gas was analyzed. (MCW)

  3. Reduced, tame and exotic fusion systems

    DEFF Research Database (Denmark)

    Andersen, K.K.S.; Oliver, Bob; Ventura, Joana

    We define here two new classes of saturated fusion systems, reduced fusion systems and tame fusion systems. These are motivated by our attempts to better understand and search for exotic fusion systems: fusion systems which are not the fusion systems of any finite group. Our main theorems say...... that every saturated fusion system reduces to a reduced fusion system which is tame only if the original one is realizable, and that every reduced fusion system which is not tame is the reduction of some exotic (nonrealizable) fusion system....

  4. Reducing pawing in horses using positive reinforcement.

    Science.gov (United States)

    Fox, Adam E; Belding, Devon L

    2015-12-01

    Aversive control is a common method to reduce undesirable behavior in horses. However, it often results in unintended negative side effects, including potential abuse of the animal. Procedures based on positive reinforcement, such as differential reinforcement of other behavior (DRO), may reduce undesirable behaviors with fewer negative consequences. The current study used DRO schedules to reduce pawing using a multiple baseline design across 3 horses. Results indicated that DRO schedules were effective at reducing pawing. However, individual differences in sensitivity to DRO and reinforcer efficacy may be important considerations.

  5. Reduced, tame and exotic fusion systems

    OpenAIRE

    Andersen, Kasper K. S.; Oliver, Bob; Ventura, Joana

    2010-01-01

    We define here two new classes of saturated fusion systems, reduced fusion systems and tame fusion systems. These are motivated by our attempts to better understand and search for exotic fusion systems: fusion systems which are not the fusion systems of any finite group. Our main theorems say that every saturated fusion system reduces to a reduced fusion system which is tame only if the original one is realizable, and that every reduced fusion system which is not tame is the reduction of some...

  6. The measurement of hydroxyl free radical scavenging activity of melanin-binding hydroxyl chloroquine by an electron spin resonance spectroscopy%电子自旋共振捕捉技术测定与黑素结合的羟基氯喹对羟自由基的清除

    Institute of Scientific and Technical Information of China (English)

    陈俊佑; 刘小明; 史赢; 雷铁池

    2012-01-01

    Objective: To determine the scavenging effects of melanin-binding hydroxyl chloroquine (HCQ) on transient hydroxyl free radical generated via the Fenton reaction, it is helpful in better understanding the mechanisms of antimalarials behind anti-inflammation and anti-photosensitivity. Methods: Transient hydroxyl free radical was generated via the Fenton reaction and trapped by DMPO. DMPO (400 mmol/L), ferrous sulfate (0.4 mmol/L), H2O2 (0.1%) and varying concentrations of melanin-binding HCQ were mixed and incubated, then sucked into a quartz capillary for 30 sec and measured by electron spin resonance (ESR). The relative amount of the radicals was estimated from the peak height of the second peak of the DMPO-OH signals in typical ESR spectra. Results: The bacteria-derived melanin (b-melanin) ranging from 20 mg/L to 100 mg/L exhibited a potent scavenging activity against hydroxyl free radical in a dose-dependent manner. 100 mg/L of b-melanin could afford a maximum scavenging activity (92.5%) against hydroxyl free radical. HCQ showed a limited and dose-independent scavenging activity toward hydroxyl radical. 50 mol/L of HCQ had the maximum scavenging rate (43.72%) against hydroxyl free radicals. The melanin-binding with 10 p,mol/L HCQ, which was equivalent to a mean blood concentration of HCQ in SLE patients receiving 400 mg of HCQ daily, demonstrated an increased scavenging activity against the radicals to compare with that of HCQ alone (P<0.05). High scavenging activity of melanin-binding HCQ against free radical was failure to reach by an increased concentration of HCQ. Conclusion; The melanin achieves an enhanced scavenging activity against hydroxyl free radical by binding with HCQ at its physiological concentration (10 μmol/L) and thereby protects skin cells from oxidative damages, which likely contributes to anti-photosensitivity of antimalarials in the treatment of cutaneous lupus erythematosus.%目的:观察与黑素结合的羟基氯喹(HCQ)对Fenton反应

  7. Simple Potentiometric Determination of Reducing Sugars

    Science.gov (United States)

    Moresco, Henry; Sanson, Pedro; Seoane, Gustavo

    2008-01-01

    In this article a potentiometric method for reducing sugar quantification is described. Copper(II) ion reacts with the reducing sugar (glucose, fructose, and others), and the excess is quantified using a copper wire indicator electrode. In order to accelerate the kinetics of the reaction, working conditions such as pH and temperature must be…

  8. An intervention to reduce playground equipment hazards

    OpenAIRE

    Roseveare, C.; Brown, J.; McIntosh, J.; Chalmers, D

    1999-01-01

    Objectives—A community intervention trial was carried out to evaluate the relative effectiveness of two methods of reducing playground hazards in schools. The study hypotheses were: (1) a health promotion programme addressing barriers to implementing the New Zealand Playground Safety Standard will reduce playground hazards and (2) the intervention programme will be more successful than providing information alone.

  9. Sulfate-reducing prokaryotes in river floodplains

    NARCIS (Netherlands)

    Miletto, M.

    2007-01-01

    This thesis constitutes a pioneer attempt at elucidating the ecology of sulfate-reducing prokaryotes in river floodplains. These are non-typical sulfate-reducing environmental settings, given the generally low sulfate concentration that characterize freshwater habitats, and river flow regulation tha

  10. Tools to Reduce Waste in Schools

    Science.gov (United States)

    US Environmental Protection Agency, 2007

    2007-01-01

    This guide was produced to help schools and school districts reduce the amount of waste they generate It shows how to start a waste reduction program or expand an existing one. The booklet shows how such programs can benefit schools, communities, and the environment by reducing, reusing, and recycling waste. Each section--schools, school…

  11. Biplots in Reduced-Rank Regression

    NARCIS (Netherlands)

    Braak, ter C.J.F.; Looman, C.W.N.

    1994-01-01

    Regression problems with a number of related response variables are typically analyzed by separate multiple regressions. This paper shows how these regressions can be visualized jointly in a biplot based on reduced-rank regression. Reduced-rank regression combines multiple regression and principal c

  12. Conformally reducible 1+3 spacetimes

    CERN Document Server

    Carot, Jaume; Tupper, Brian O J

    2013-01-01

    Spacetimes which are conformally related to reducible 1+3 spacetimes are considered. We classify these spacetimes according to the conformal algebra of the underlying reducible spacetime, giving in each case canonical expressions for the metric and conformal Killing vectors, and provide physically meaningful examples.

  13. Conformally reducible 1+3 spacetimes

    Energy Technology Data Exchange (ETDEWEB)

    Carot, Jaume [Departament de Fisica, Universitat de les Illes Balears, Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca (Spain); Keane, Aidan J [87 Carlton Place, Glasgow G5 9TD, Scotland (United Kingdom); Tupper, Brian O J [Department of Mathematics and Statistics, University of New Brunswick, Fredericton, NB E3B 5A3 (Canada)], E-mail: jcarot@uib.es, E-mail: aidan@countingthoughts.com, E-mail: bt32@rogers.com

    2008-03-07

    Spacetimes which are conformally related to reducible 1+3 spacetimes are considered. We classify these spacetimes according to the conformal algebra of the underlying reducible spacetime, giving in each case canonical expressions for the metric and conformal Killing vectors, and providing physically meaningful examples.

  14. The Consumer's Handbook for Reducing Solid Waste.

    Science.gov (United States)

    Environmental Protection Agency, Washington, DC.

    This profusely illustrated and informally written booklet describes how people can help solve a growing problem--garbage. The following 12 tips are presented: (1) Reduce the amount of unnecessary packaging; (2) Adopt practices that reduce waste toxicity; (3) Consider reusable products; (4) Maintain and repair durable products; (5) Reuse bags,…

  15. Chitosan-supported Borohydride Reducing Agent

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A new chitosan-supported borohydride reducing reagent (CBER) was prepared by treatment of KBH4 with the resin of chitosan derivative, which was first synthesized fiom the reaction of cross-linked chitosan microsphere with glycidyl trimethylammonium chloride. CBER could reduce aromatic carbonyl compound to corresponding alcohol.

  16. DYNAMICAL BALANCE STUDY OF RING REDUCER

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The basic structure of epicyclical gear transmission with inner teeth of single-ring, double-ring, three-ring and four-ring reducer are analyzed. The force analysis model of ring reducer is built. Following this, it is concluded that the present ring reducers have the problem that the inertia force or the inertia moment is lopsided. On the base of analysis and calculation the balanced ring reducer which can realize the balance of inertia force and inertia moment is brought forward, and so is its concrete realizing step. The specimen of the balanced ring reducer is designed and manufactured; the experiment is carried out on the gear transmission test bench. Compared with other ring reducer of the same power, the balanced ring reducer has many advantages, such as low vibration noise, low cost and less production difficulty and less heat. It is the substitute of other ring reducer of the same kind. Therefore, it has important theoretic significance and highly practical engineering value.

  17. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.

    Directory of Open Access Journals (Sweden)

    Patricia A Reis

    Full Text Available Neurological impairments are frequently detected in children surviving cerebral malaria (CM, the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW mice with Plasmodium berghei ANKA (PbA or a lethal strain of Plasmodium yoelii XL (PyXL, respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

  18. Multiclass Reduced-Set Support Vector Machines

    Science.gov (United States)

    Tang, Benyang; Mazzoni, Dominic

    2006-01-01

    There are well-established methods for reducing the number of support vectors in a trained binary support vector machine, often with minimal impact on accuracy. We show how reduced-set methods can be applied to multiclass SVMs made up of several binary SVMs, with significantly better results than reducing each binary SVM independently. Our approach is based on Burges' approach that constructs each reduced-set vector as the pre-image of a vector in kernel space, but we extend this by recomputing the SVM weights and bias optimally using the original SVM objective function. This leads to greater accuracy for a binary reduced-set SVM, and also allows vectors to be 'shared' between multiple binary SVMs for greater multiclass accuracy with fewer reduced-set vectors. We also propose computing pre-images using differential evolution, which we have found to be more robust than gradient descent alone. We show experimental results on a variety of problems and find that this new approach is consistently better than previous multiclass reduced-set methods, sometimes with a dramatic difference.

  19. Novel Reduced Parts Online Uninterruptible Power Supply

    Directory of Open Access Journals (Sweden)

    Bahram Ashrafi

    2012-01-01

    Full Text Available This paper presents design consideration and performance analysis of novel reduced parts online three-phase uninterruptible power supply (UPS system. The proposed UPS system is based on reduced switch count dual bridge matrix converter. It employs only six power switches and results in reducing the cost of the system compared to conventional online UPS topologies, while achieving excellent performance. The performance of the proposed system is evaluated through simulation in terms of input/output waveforms quality and shows the viability of topology.

  20. Reduced Baroclinicity During Martian Global Dust Storms

    Science.gov (United States)

    Battalio, Joseph; Szunyogh, Istvan; Lemmon, Mark

    2015-11-01

    The eddy kinetic energy equation is applied to the Mars Analysis Correction Data Assimilation (MACDA) dataset during the pre-winter solstice period for the northern hemisphere of Mars. Traveling waves are triggered by geopotential flux convergence, grow baroclinically, and decay barotropically. Higher optical depth increases the static stability, which reduces vertical and meridional heat fluxes. Traveling waves during a global dust storm year develop a mixed baroclinic/barotropic growth phase before decaying barotropically. Baroclinic energy conversion is reduced during the global dust storm, but eddy intensity is undiminished. Instead, the frequency of storms is reduced due to a stabilized vertical profile.

  1. Reducing urinary tract infections in catheterised patients.

    Science.gov (United States)

    Howe, Pam; Adams, John

    2015-01-20

    Urinary tract infections in catheterised patients continue to present a challenge in reducing healthcare-associated infection. In this article, an infection prevention and control team in one NHS trust reports on using audit results to focus attention on measures to reduce bacterial infections. Educational initiatives have an important role in reducing infection, but there is no single solution to the problem. Practice can be improved using a multi-targeted approach, peer review and clinical audit to allow for shared learning and experiences. These, along with informal education in the clinical area and more formal classroom lectures, can ultimately lead to improved patient outcomes. PMID:25585767

  2. Electronic states in systems of reduced dimensionality

    International Nuclear Information System (INIS)

    This report briefly discusses the following research: magnetically modulated systems, inelastic magnetotunneling, ballistic transport review, screening in reduced dimensions, raman and electron energy loss spectroscopy; and ballistic quantum interference effects. (LSP)

  3. REDUCING TOXICITY CHEMICALS PLANT PROTECTION PRODUCTS

    OpenAIRE

    Litvishko, Valery; Myaskovskaya, Tatiana

    2014-01-01

    The samples of microencapsulated pesticide have been investigated in acute experiments on laboratory animals. The results of the research have determined that microencapsulation can reduce toxicity of plant protection chemicals.

  4. Spontaneously reduced isolated orbital roof fracture.

    Science.gov (United States)

    Itinteang, Tinte; Lambe, Gerald Francis; MacKinnon, Craig; Agir, Hakan

    2012-07-01

    We report a case of a spontaneously reduced isolated orbital roof blow-in fracture with resolution of associated diplopia and blepharoptosis highlighting the need for a low threshold for reimaging this cohort of facial fracture patients. PMID:22801127

  5. Cogeneration, renewables and reducing greenhouse gas emissions

    International Nuclear Information System (INIS)

    The MENSA model is used to assess the potential role of cogeneration and selected new renewable energy technologies in cost-effectively reducing Greenhouse gas emissions. The model framework for analyzing these issues is introduced, together with an account of relevant aspects of its application. In the discussion of selected new renewable energy technologies, it is shown how microeconomic reform may encourage these technologies and fuels, and thereby reduce sector wide carbon dioxide emissions. Policy scenarios modelled are described and the simulation results are presented. Certain interventions in microeconomic reform may result in economic benefits while also reducing emissions: no regrets' opportunities. Some renewable energy technologies are also shown to be cost-effective in the event that targets and timetables for reducing Greenhouse gas emissions are imposed. However, ad hoc interventions in support of particular renewables options are unlikely to be consistent with a least cost approach to achieving environmental objectives. (author). 5 tabs., 5 figs., 21 refs

  6. Conformally reducible 2+2 spacetimes

    Energy Technology Data Exchange (ETDEWEB)

    Carot, Jaume [Departament de Fisica, Universitat de les Illes Balears, Cra. Valldemossa km 7.5, E-07071 Palma de Mallorca (Spain); Tupper, Brian O J [Department of Mathematics and Statistics, University of New Brunswick, Fredericton, NB E3B 5A3 (Canada)

    2002-08-07

    Spacetimes which are conformal to 2+2 reducible spacetimes are considered. We classify them according to their conformal algebra, giving in each case explicit expressions for the metric and conformal Killing vectors, and providing physically meaningful examples.

  7. Conformally reducible 2+2 spacetimes

    CERN Document Server

    Carot, J

    2002-01-01

    Spacetimes which are conformal to 2+2 reducible spacetimes are considered. We classify them according to their conformal algebra, giving in each case explicit expressions for the metric and conformal Killing vectors, and providing physically meaningful examples.

  8. Vaccine Reduces HPV Infections in Young Men

    Science.gov (United States)

    An international randomized clinical trial has shown that the vaccine Gardasil can reduce the incidence of anogenital human papillomavirus (HPV) infections in young men 16 to 26 years of age at the time of vaccination.

  9. Do conditional benefits reduce equilibrium unemployment?

    NARCIS (Netherlands)

    F. van der Ploeg

    2006-01-01

    Although unconditional unemployment benefits destroy jobs in competitive and noncompetitive labor markets, conditional benefits can spur job growth in noncompetitive labor markets. Unconditional benefits reduce the penalty of shirking and misconduct, while conditional benefits increase this penalty.

  10. Reduced sulfur compound oxidation by Thiobacillus caldus.

    OpenAIRE

    Hallberg, K. B.; Dopson, M; Lindström, E B

    1996-01-01

    The oxidation of reduced inorganic sulfur compounds was studied by using resting cells of the moderate thermophile Thiobacillus caldus strain KU. The oxygen consumption rate and total oxygen consumed were determined for the reduced sulfur compounds thiosulfate, tetrathionate, sulfur, sulfide, and sulfite in the absence and in the presence of inhibitors and uncouplers. The uncouplers 2,4-dinitrophenol and carbonyl cyanide m-chlorophenyl-hydrazone had no affect on the oxidation of thiosulfate, ...

  11. Programming MapReduce with Scalding

    CERN Document Server

    Chalkiopoulos, Antonios

    2014-01-01

    This book is an easy-to-understand, practical guide to designing, testing, and implementing complex MapReduce applications in Scala using the Scalding framework. It is packed with examples featuring log-processing, ad-targeting, and machine learning. This book is for developers who are willing to discover how to effectively develop MapReduce applications. Prior knowledge of Hadoop or Scala is not required; however, investing some time on those topics would certainly be beneficial.

  12. Evaluating Active Interventions to Reduce Student Procrastination

    OpenAIRE

    Martin, Joshua Deckert

    2015-01-01

    Procrastination is a pervasive problem in education. In computer science, procrastination and lack of necessary time management skills to complete programming projects are viewed as primary causes of student attrition. The most effective techniques known to reduce procrastination are resource-intensive and do not scale well to large classrooms. In this thesis, we examine three course interventions designed to both reduce procrastination and be scalable for large classrooms. Reflective writ...

  13. IHadoop: Asynchronous iterations for MapReduce

    KAUST Repository

    Elnikety, Eslam Mohamed Ibrahim

    2011-11-01

    MapReduce is a distributed programming frame-work designed to ease the development of scalable data-intensive applications for large clusters of commodity machines. Most machine learning and data mining applications involve iterative computations over large datasets, such as the Web hyperlink structures and social network graphs. Yet, the MapReduce model does not efficiently support this important class of applications. The architecture of MapReduce, most critically its dataflow techniques and task scheduling, is completely unaware of the nature of iterative applications; tasks are scheduled according to a policy that optimizes the execution for a single iteration which wastes bandwidth, I/O, and CPU cycles when compared with an optimal execution for a consecutive set of iterations. This work presents iHadoop, a modified MapReduce model, and an associated implementation, optimized for iterative computations. The iHadoop model schedules iterations asynchronously. It connects the output of one iteration to the next, allowing both to process their data concurrently. iHadoop\\'s task scheduler exploits inter-iteration data locality by scheduling tasks that exhibit a producer/consumer relation on the same physical machine allowing a fast local data transfer. For those iterative applications that require satisfying certain criteria before termination, iHadoop runs the check concurrently during the execution of the subsequent iteration to further reduce the application\\'s latency. This paper also describes our implementation of the iHadoop model, and evaluates its performance against Hadoop, the widely used open source implementation of MapReduce. Experiments using different data analysis applications over real-world and synthetic datasets show that iHadoop performs better than Hadoop for iterative algorithms, reducing execution time of iterative applications by 25% on average. Furthermore, integrating iHadoop with HaLoop, a variant Hadoop implementation that caches

  14. New approaches to reduce radiation exposure.

    Science.gov (United States)

    Hill, Kevin D; Einstein, Andrew J

    2016-01-01

    Exposure to ionizing radiation is associated with a long-term risk of health effects, including cancer. Radiation exposure to the U.S. population from cardiac imaging has increased markedly over the past three decades. Initiatives to reduce radiation exposure have focused on the tenets of appropriate study "justification" and "optimization" of imaging protocols. This article reviews ways to optimally reduce radiation dose across the spectrum of cardiac imaging.

  15. Reduced span spray – Part 1: Retention

    OpenAIRE

    Massinon, Mathieu; De Cock, Nicolas; Ouled Taleb Salah, Sofiene; Lebeau, Frédéric

    2016-01-01

    Maximising treatment efficiency for a given target lies mainly on depositing a maximum part of the spray volume within an optimal droplet size range, which has to be as narrow as possible to reduce retention variability and drift issues. The present work focuses on exploring the effect of span factor of the droplet size distribution on the final retention by a 3D target plant using a modelling approach with the final aim of guiding the development of a reduced span nozzle (Redu...

  16. Acetate reduces microglia inflammatory signaling in vitro

    OpenAIRE

    Soliman, Mahmoud L; Puig, Kendra L.; Combs, Colin K.; Rosenberger, Thad A.

    2012-01-01

    Acetate supplementation increases brain acetyl-CoA and histone acetylation and reduces lipopolysaccharide (LPS)-induced neuroglial activation and interleukin (IL)-1β expression in vivo. To determine how acetate imparts these properties, we tested the hypothesis that acetate metabolism reduces inflammatory signaling in microglia. To test this, we measured the effect acetate treatment had on cytokine expression, mitogen-activated protein kinase (MAPK) signaling, histone H3 at lysine 9 acetylati...

  17. Laser welding in a reduced gravity environment

    Science.gov (United States)

    Workman, Gary L.; Kaukler, William F.

    1992-01-01

    Preliminary results on the effects of reduced gravity on laser welding of stainless steel and other materials are reported. Laser welding experiments using a low power (10-18 watts) Nd-YAG laser have been performed on the NASA KC-135, which flies parabolic maneuvers to simulate reduced gravity conditions. Experiments on 0.005-0.010 inch thick stainless steel samples displayed a pronounced change in weld bead width, depth of penetration and surface ripple with changes in gravity level.

  18. Boiler burden reduced at Bedford site.

    Science.gov (United States)

    Horsley, Chris

    2011-10-01

    With the NHS aiming to reduce its 2007 carbon footprint by 10% by 2015, Chris Horsley, managing director of Babcock Wanson UK, a provider of industrial boilers and burners, thermal oxidisers, air treatment, water treatment, and associated services, looks at how one NHS Trust has approached the challenge, and considerably reduced its carbon emissions, by refurbishing its boiler house and moving from oil to gas-fired steam generation. PMID:22049674

  19. Contralateral Risk-Reducing Mastectomy: Review of Risk Factors and Risk-Reducing Strategies

    OpenAIRE

    Basu, N. N.; Barr, L; Ross, G. L.; Evans, D. G.

    2015-01-01

    Rates of contralateral risk-reducing mastectomy have increased substantially over the last decade. Surgical oncologists are often in the frontline, dealing with requests for this procedure. This paper reviews the current evidence base regarding contralateral breast cancer, assesses the various risk-reducing strategies, and evaluates the cost-effectiveness of contralateral risk-reducing mastectomy.

  20. Evolution of technetium speciation in reducing grout

    Energy Technology Data Exchange (ETDEWEB)

    Lukens, Wayne W.; Bucher, Jerome J.; Shuh, David K.; Edelstein,Norman M.

    2003-11-24

    Cementitious waste forms (CWFs) are an important component of the strategy to immobilize high-level nuclear waste resulting from plutonium production by the U.S. Department of Energy (DOE). Technetium (99Tc) is an abundant fission product of particular concern in CWFs due to the high solubility and mobility of pertechnetate, TcO4-, the stable form of technetium in aerobic environments. CWFs can more effectively immobilize 99Tc if they contain additives that reduce mobile TcO4- to immobile Tc(IV) species. Leaching of 99Tc from reducing CWFs that contain Tc(IV) is much slower than for CWFs containing TcO4-. Previous X-ray absorption fine structure (XAFS) studies showed that the Tc(IV) species were oxidized to TcO4- in reducing grout samples prepared on a laboratory scale. Whether the oxidizer was atmospheric O2 or NO3- in the waste simulant was not determined. In actual CWFs, rapid oxidation of Tc(IV) by NO3- would be a concern, whereas oxidation by atmospheric O2 would be of less concern due to the slow diffusion and reaction of O2 with the reducing CWF. To address this uncertainty, two series of reducing grouts were prepared using TcO4- containing waste simulants with and without NO3-. In the first series of samples, the TcO4- was completely reduced using Na2S, and the samples were placed in containers that permitted O2 diffusion. In these samples, all of the technetium was initially present as aTc(IV) sulfide compound, TcSx, which was characterized using extended X-ray absorption fine structure (EXAFS) spectroscopy, and is likely Tc2S7. The TcSx initially present in the grout samples was steadily oxidized over 4 years. In the second series of samples, all of the TcO4- was not initially reduced, and the grout samples were placed in airtight containers. In these samples, the remaining TcO4- continued to be reduced as the samples aged, presumably due to the presence of reducing blast furnace slag. When samples in the second series were exposed to atmosphere, the

  1. Bioremediation: Effectiveness in reducing the ecological impact

    International Nuclear Information System (INIS)

    Bioremediation becomes an important technique in oil spill combat programmes. The purpose is to shorten the exposure time of biota to oil compounds, in order to reduce long term environmental effects. Although bioremediation products have the advantage of stimulating the natural capacity to degrade oil, there are some limitations to be considered. Application as a technique for first emergency actions following an oil spill is not effective, and can therefore be no alternative for dispersion or mechanical removal of floating or freshly stranded oil slicks. Acute toxic effects are related to the short term exposure to unweathered oils. An immediate removal of oil is necessary to reduce the extent of the environmental impact of an oil spill. Physical processes (transport, dilution and evaporation) are determining the initial fate of environmentally released oil. Biodegradation only becomes important as a process of removing oil in the next phase. It is the only effective way to further reduce the concentration of oil that is left in (intertidal) coastal areas. Bioremediation thus reduces the duration of the environmental impact of an oil spill. This is especially important in ecosystems with a low recovery potential (e.g., salt marshes, rocky shores). The experimental evaluation of bioremediation products is mainly based on the capacity to reduce fresh oil and the acute toxicity of the product itself, rather than on the capacity to enhance the further reduction of weathered oil and the toxicological consequences of higher release rates of intermediate metabolites produced during the biotransformation processes

  2. Moral elevation reduces prejudice against gay men.

    Science.gov (United States)

    Lai, Calvin K; Haidt, Jonathan; Nosek, Brian A

    2014-01-01

    Disgust is linked to social evaluation. People with higher disgust sensitivity exhibit more sexual prejudice, and inducing disgust increases sexual prejudice. We tested whether inducing moral elevation, the theoretical opposite of disgust, would reduce sexual prejudice. In four studies (N = 3622), we induced elevation with inspiring videos and then measured sexual prejudice with implicit and explicit measures. Compared to control videos that elicited no particular affective state, we found that elevation reduced implicit and explicit sexual prejudice, albeit very slightly. No effect was observed when the target of social evaluation was changed to race (Black-White). Inducing amusement, another positive emotion, did not significantly affect sexual prejudice. We conclude that elevation weakly but reliably reduces prejudice towards gay men.

  3. Arbuscular mycorrhizas reduce nitrogen loss via leaching.

    Directory of Open Access Journals (Sweden)

    Hamid R Asghari

    Full Text Available The capacity of mycorrhizal and non-mycorrhizal root systems to reduce nitrate (NO₃⁻ and ammonium (NH₄⁺ loss from soils via leaching was investigated in a microcosm-based study. A mycorrhiza defective tomato mutant and its mycorrhizal wildtype progenitor were used in this experiment in order to avoid the indirect effects of establishing non-mycorrhizal control treatments on soil nitrogen cycling and the wider soil biota. Mycorrhizal root systems dramatically reduced nitrate loss (almost 40 times less via leaching, compared to their non-mycorrhizal counterparts, following a pulse application of ammonium nitrate to experimental microcosms. The capacity of AM to reduce nutrient loss via leaching has received relatively little attention, but as demonstrated here, can be significant. Taken together, these data highlight the need to consider the potential benefits of AM beyond improvements in plant nutrition alone.

  4. Reduced herbicide rates: present and future

    DEFF Research Database (Denmark)

    Kudsk, Per

    2014-01-01

    rates will result in maximum effects, 2) that the conditions at and around the time of application, e.g. growth stage of weeds, crop vigour and climatic condition are optimum promoting the activity of the herbicide and thus allows for the use of reduced herbicides rates, or 3) that less than maximum......Applying herbicides at rates lower than the label recommendation has been the rule rather than the exception in Denmark since the late 1980’s. Justifications for reducing herbicide rates can be 1) that the dominant weed species in the field are very susceptible to the herbicide, i.e. even reduced...... effects are accepted because the weed flora is not considered to have a significant effect on crop yield. “Crop Protection Online-Weed” (CPO-Weed) is a web-based decision support system that was developed to support farmers in their choice of herbicide and herbicide rate. CPOWeed will, based...

  5. Active structures to reduce torsional vibrations

    Science.gov (United States)

    Matthias, M.; Schlote, D.; Atzrodt, H.

    2013-03-01

    This paper describes the development of different active measures to reduce torsional vibrations in power trains. The measures are based on concepts developed for active mounts to reduce the transmission of structure-borne sound. To show the potential of these active measures and investigate their mode of operation to influence torsional vibrations, numerical simulations of powertrains with different active measures were done. First experimental results from tests on an experimental (reduced size) power train were used to align the numerical models. The work was done within the project 'LOEWE-Zentrum AdRIA: Adaptronik - Research, Innovation, Application' funded by the German federal state of Hessen, and the Project AKTos: 'Active control of torsional vibrations by coupling elements' placed in the research Framework program 'Navigation and Maritime Technology for the 21st Century' funded by the German Federal Ministry of Economics and Technology.

  6. Manager's guide to reducing dental hygiene turnover.

    Science.gov (United States)

    Loiacono, C

    1989-09-01

    The purpose of this paper is to address the issue of dental hygiene turnover and provide managers with strategies for preventing and reducing turnover. Employee turnover is a problem which affects dental health care delivery and the health of the public. Employee turnover is costly to work settings and creates a stressful working environment which has an impact on professional-client relationships. To reduce or prevent turnover in a private practice setting, office managers must be informed about the causes and effects of this problem and be able to implement solutions. Some strategies managers can use to reduce turnover are hiring employees who have the same goals as the organization; improving the working climate; rewarding longevity; encouraging the active participation of all staff members in office management; improving office communication; and providing opportunities for self-growth, recognition, and greater responsibilities.

  7. Reducing the convective losses of cavity receivers

    Science.gov (United States)

    Flesch, Robert; Grobbel, Johannes; Stadler, Hannes; Uhlig, Ralf; Hoffschmidt, Bernhard

    2016-05-01

    Convective losses reduce the efficiency of cavity receivers used in solar power towers especially under windy conditions. Therefore, measures should be taken to reduce these losses. In this paper two different measures are analyzed: an air curtain and a partial window which covers one third of the aperture opening. The cavity without modifications and the usage of a partial window were analyzed in a cryogenic wind tunnel at -173°C. The cryogenic environment allows transforming the results from the small model cavity to a large scale receiver with Gr≈3.9.1010. The cavity with the two modifications in the wind tunnel environment was analyzed with a CFD model as well. By comparing the numerical and experimental results the model was validated. Both modifications are capable of reducing the convection losses. In the best case a reduction of about 50 % was achieved.

  8. Nature of Reduced Carbon in Martian Meteorites

    Science.gov (United States)

    Gibson, Everett K., Jr.; McKay, D. S.; Thomas-Keprta, K. L.; Clemett, S. J.; White, L. M.

    2012-01-01

    Martian meteorites provide important information on the nature of reduced carbon components present on Mars throughout its history. The first in situ analyses for carbon on the surface of Mars by the Viking landers yielded disappointing results. With the recognition of Martian meteorites on Earth, investigations have shown carbon-bearing phases exist on Mars. Studies have yielded presence of reduced carbon, carbonates and inferred graphitic carbon phases. Samples ranging in age from the first approximately 4 Ga of Mars history [e.g. ALH84001] to nakhlites with a crystallization age of 1.3 Ga [e.g. Nakhla] with aqueous alteration processes occurring 0.5-0.7 Ga after crystallizaton. Shergottites demonstrate formation ages around 165-500 Ma with younger aqueous alterations events. Only a limited number of the Martian meteorites do not show evidence of significance terrestrial alterations. Selected areas within ALH84001, Nakhla, Yamato 000593 and possibly Tissint are suitable for study of their indigenous reduced carbon bearing phases. Nakhla possesses discrete, well-defined carbonaceous phases present within iddingsite alteration zones. Based upon both isotopic measurements and analysis of Nakhla's organic phases the presence of pre-terrestrial organics is now recognized. The reduced carbon-bearing phases appear to have been deposited during preterrestrial aqueous alteration events that produced clays. In addition, the microcrystalline layers of Nakhla's iddingsite have discrete units of salt crystals suggestive of evaporation processes. While we can only speculate on the origin of these unique carbonaceous structures, we note that the significance of such observations is that it may allow us to understand the role of Martian carbon as seen in the Martian meteorites with obvious implications for astrobiology and the pre-biotic evolution of Mars. In any case, our observations strongly suggest that reduced organic carbon exists as micrometer- size, discrete structures

  9. Reducing Transmitted Vibration Using Delayed Hysteretic Suspension

    Directory of Open Access Journals (Sweden)

    Lahcen Mokni

    2011-01-01

    Full Text Available Previous numerical and experimental works show that time delay technique is efficient to reduce transmissibility of vibration in a single pneumatic chamber by controlling the pressure in the chamber. The present work develops an analytical study to demonstrate the effectiveness of such a technique in reducing transmitted vibrations. A quarter-car model is considered and delayed hysteretic suspension is introduced in the system. Analytical predictions based on perturbation analysis show that a delayed hysteretic suspension enhances vibration isolation comparing to the case where the nonlinear damping is delay-independent.

  10. Reduced Basis Method for Nanodevices Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Pau, George Shu Heng

    2008-05-23

    Ballistic transport simulation in nanodevices, which involves self-consistently solving a coupled Schrodinger-Poisson system of equations, is usually computationally intensive. Here, we propose coupling the reduced basis method with the subband decomposition method to improve the overall efficiency of the simulation. By exploiting a posteriori error estimation procedure and greedy sampling algorithm, we are able to design an algorithm where the computational cost is reduced significantly. In addition, the computational cost only grows marginally with the number of grid points in the confined direction.

  11. Reduced Multiplicative Tolerance Ranking and Applications

    Directory of Open Access Journals (Sweden)

    Sebastian Sitarz

    2013-02-01

    Full Text Available In this paper a reduced multiplicative tolerance - a measure of sensitivity analysis in multi-objective linear programming (MOLP is presented. By using this new measure a method for ranking the set of efficient extreme solutions is proposed. The idea is to rank these solutions by values of the reduced tolerance. This approach can be applied to many MOLP problems, where sensitivity analysis is important for a decision maker. In the paper, applications of the presented methodology are shown in the market model and the transportation problem.

  12. Comments on the height reducing property

    CERN Document Server

    Akiyama, Shigeki

    2012-01-01

    A complex number alpha is said to satisfy the height reducing property if there is a finite subset F of the ring Z of the rational integers such that Z[alpha]=F[alpha]. This problem of finding F has been considered by several authors, especially in contexts related to self affine tilings, and expansions of real numbers in non-integer bases. We continue, in this note, the description of the numbers satisfying the height reducing property, and we specify a related characterization of the roots of integer polynomials with dominant term.

  13. Reducing parametric backscattering by polarization rotation

    CERN Document Server

    Barth, Ido

    2016-01-01

    When a laser passes through underdense plasmas, Raman and Brillouin Backscattering can reflect a substantial portion of the incident laser energy. This is a major loss mechanism, for example, in inertial confinement fusion. However, by slow rotation of the incident linear polarization, the overall reflectivity can be reduced significantly. Particle in cell simulations show that, for parameters similar to those of indirect drive fusion experiments, polarization rotation reduces the reflectivity by a factor of $5$. A general, fluid-model based, analytical estimation for the reflectivity reduction agrees with simulations.

  14. Experimental knee pain reduces muscle strength

    DEFF Research Database (Denmark)

    Henriksen, Marius; Mortensen, Sara Rosager; Aaboe, Jens;

    2011-01-01

    experimental knee pain in healthy volunteers, and if these changes were associated with the pain intensities. In a crossover study, 18 healthy subjects were tested on 2 different days. Using an isokinetic dynamometer, maximal muscle strength in knee extension and flexion was measured at angular velocities 0....... Knee pain reduced the muscle strength by 5 to 15% compared to the control conditions (P <.001) in both knee extension and flexion at all angular velocities. The reduction in muscle strength was positively correlated to the pain intensity. Experimental knee pain significantly reduced knee extension and...

  15. The Assignment Game : The Reduced Game

    OpenAIRE

    Owen, Guillermo

    1992-01-01

    Let v be an assignment game. For a given reference payoff vector (x; y), and a coalition S, bargaining within the coalition can be represented by either the reduced game or the derived game. It is known that the reduced game need not be an assignment game (in fact, it need not be super additive) while the derived game is another assignment game, with modified reservation prices. We prove that, when the reference vector is in the core of the game, the derived game is the super additive cover o...

  16. Restricted fish feeding reduces cod otolith opacity

    DEFF Research Database (Denmark)

    Høie, H.; Folkvord, A.; Mosegaard, Henrik;

    2008-01-01

    The purpose of this work was to examine the effect of reduced feeding and constant temperature on cod otolith opacity. Three groups of juvenile cod were given restricted food rations at different times for 4 months, resulting in depressed somatic growth. Otolith opacity was measured on pictures...... in otolith opacity were found between individual fish both within groups and between groups. In two of the three groups significantly more translucent otolith material was deposited in response to reduced feeding. Our results show that variations in feeding and hence fish growth resulted in variation...

  17. Device and Method for Reducing Aircraft Noise

    Science.gov (United States)

    Streett, Craig L. (Inventor); Lin, John C. (Inventor)

    2002-01-01

    A noise abatement device that is positioned adjacent to a body. The noise abatement device generally includes tabs or cavities which thicken the shear layer created by fluid flow over, around, or near the body, by creating horseshoe-shaped vortices; this thickening of the shear layer reduces the strength of fluctuations in the flow which produce noise.

  18. 77 FR 47328 - Reducing Regulatory Burden

    Science.gov (United States)

    2012-08-08

    ... health and safety, and other advantages; distributive impacts; and equity). The regulatory process... businesses and the public. Agencies consider low-cost approaches that reduce burdens and maintain flexibility...-regulatory-system . The Department is committed to maintaining a consistent culture of retrospective...

  19. 77 FR 28518 - Reducing Regulatory Burden

    Science.gov (United States)

    2012-05-15

    ..., and other advantages; distributive impacts; and equity). The regulatory process encourages public..., simplify, and harmonize regulations to reduce costs and promote certainty for businesses and the public... culture of retrospective review and analysis. DOE will continually engage in review of its rules...

  20. Chemicals Reduce Need To Mow Grass

    Science.gov (United States)

    Humphrys, Brooks; Farley, Max; Gast, Larry J.

    1993-01-01

    Brief report discusses use of herbicides Roundup(R), Campaign(R), and Oust(R) to retard growth of Argentine bahia grass. Herbicide applied by use of spraying apparatus pulled by tractor. "Chemical mowing" keeps grass at "freshly mowed" height with less mechanical mowing. Applied to grass on shoulders of roads, reducing time spent on mowing.

  1. Scientist Researches Way to Reduce Global Warming

    Science.gov (United States)

    For the last four years, scientists at the USDA, Agricultural Research Service, Northern Plains Agricultural Research Laboratory have been searching for alternative soil and crop management practices to reduce greenhouse gas emissions and increase carbon and nitrogen sequestration. “If we can redu...

  2. Reducing the Risk of Methadone Overdose

    Centers for Disease Control (CDC) Podcasts

    2012-07-03

    This podcast is based on the July 2012 CDC Vital Signs report. Approximately 14 people die every day of overdoses related to methadone. Listen to learn how to reduce your risk of an overdose.  Created: 7/3/2012 by Centers for Disease Control and Prevention (CDC).   Date Released: 7/3/2012.

  3. QUIESST Guidebook to Noise Reducing Devices optimisation

    NARCIS (Netherlands)

    Clairbois, J.P.; Roo, F. de; Garai, M.; Conter, M.; Defrance, J.; Oltean-Dumbrava, C.A.; Durso, C.

    2012-01-01

    The aim of this guidebook is to become a reference tool for noise mitigation through a better use of Noise Reducing Devices (NRD) (e.g.: Noise Barriers or sound Absorptive Claddings). It targets all the stakeholders involved in NRD projects (designers, manufacturers, authorities, construction compan

  4. Reducing consumption by way of energy recovery

    Energy Technology Data Exchange (ETDEWEB)

    Reichert, K.

    1983-01-01

    The article deals with the recovery of the consumed energy from waste air. Schematical presentations of the cooling systems at printing machines in connection with the heat flow of machine-air-water-heat pump-heating are shown. There are preconditions of integrated cooling systems and modules for rational energy utilization. Energy costs and ways of reducing operational costs are also touched.

  5. Sodium Valproate Withdrawal Correlates with Reduced Aggression

    Science.gov (United States)

    Pritchard, Duncan; Hoerger, Marguerite; Dyer, Tim; Graham, Nicola; Penney, Heather; Mace, F. Charles

    2014-01-01

    People with learning disabilities are sometimes prescribed psychotropic medication to help manage their challenging behaviour. This case study describes how a multicomponent behavioural intervention in conjunction with the systematic withdrawal of sodium valproate was strongly correlated with reduced aggression. No symptoms of bipolar disorder or…

  6. Sexual Harassment at Camp: Reducing Liability.

    Science.gov (United States)

    Oakleaf, Linda; Grube, Angela Johnson

    2003-01-01

    Employers are responsible for sexual harassment perpetrated by a supervisor. Camps may be responsible for sexual harassment between campers. Steps to reduce liability include providing multiple channels for reporting sexual harassment; having written policies prohibiting sexual harassment and procedures for reporting it; posting these policies and…

  7. Reduced Voltage Scaling in Clock Distribution Networks

    Directory of Open Access Journals (Sweden)

    Khader Mohammad

    2009-01-01

    Full Text Available We propose a novel circuit technique to generate a reduced voltage swing (RVS signals for active power reduction on main buses and clocks. This is achieved without performance degradation, without extra power supply requirement, and with minimum area overhead. The technique stops the discharge path on the net that is swinging low at a certain voltage value. It reduces active power on the target net by as much as 33% compared to traditional full swing signaling. The logic 0 voltage value is programmable through control bits. If desired, the reduced-swing mode can also be disabled. The approach assumes that the logic 0 voltage value is always less than the threshold voltage of the nMOS receivers, which eliminate the need of the low to high voltage translation. The reduced noise margin and the increased leakage on the receiver transistors using this approach have been addressed through the selective usage of multithreshold voltage (MTV devices and the programmability of the low voltage value.

  8. How Does Distinctive Processing Reduce False Recall?

    Science.gov (United States)

    Hunt, R. Reed; Smith, Rebekah E.; Dunlap, Kathryn R.

    2011-01-01

    False memories arising from associatively related lists are a robust phenomenon that resists many efforts to prevent it. However, a few variables have been shown to reduce this form of false memory. Explanations for how the reduction is accomplished have focused on either output monitoring processes or constraints on access, but neither idea alone…

  9. Reduced Magnetohydrodynamic Equations in Toroidal Geometry

    Institute of Scientific and Technical Information of China (English)

    REN Shen-Ming; YU Guo-Yang

    2001-01-01

    By applying a new assumption of density, I.e. R2 p = const, the continuity equation is satisfied to the order ofe2`+with e being the inverse aspect ratio. In the case of large aspect ratio, a set of reduced magnetohydrodynamicequations in toroidal geometry are obtained. The new assumption about the density is supported by experimentalobservation to some extent.

  10. Reducing Dogmatism among Undergraduate Counselor Trainees.

    Science.gov (United States)

    Parkay, Forrest W.

    Previous research has emphasized the significant negative correlation between counselor effectiveness and dogmatism, or closemindedness. To reduce levels of dogmatism in counselor trainees, a program was developed and tested at Southwest Texas State University. The new course, "Guidance to Meet the Needs of Multicultural Students," gave counseling…

  11. Reducing Depression in Pregnancy: Designing Multimodel Interventions.

    Science.gov (United States)

    Cunningham, Maddy; Zayas, Luis H.

    2002-01-01

    High levels of stress on low-income, inner-city women from ethnic minority groups often causes both poor maternal functioning and infant development outcomes. This article reviews literature that proposes using several social work treatment options instead a single approach to reduce maternal depression, expand mothers' social networks, and…

  12. Strategies for Reducing Text Book Costs

    Science.gov (United States)

    Board of Governors, State University System of Florida, 2008

    2008-01-01

    In recent years, the price of college textbooks has become a growing concern for students and others who care about keeping college costs affordable. As policymakers and higher education systems explore the issue further, there are actions that can be taken immediately on college campuses to reduce the cost of textbooks. This brief presents…

  13. Ultrametric fixed points in reduced axiomatic systems

    OpenAIRE

    Turinici, Mihai

    2015-01-01

    The Brezis-Browder ordering principle [Advances Math., 21 (1976), 355-364] is used to get a proof, in the reduced axiomatic system (ZF-AC+DC), of a fixed point result [in the complete axiomatic system (ZF)] over Cantor complete ultrametric spaces due to Petalas and Vidalis [Proc. Amer. Math. Soc., 118 (1993), 819-821].

  14. Reducing Research Anxiety among MSW Students

    Science.gov (United States)

    Einbinder, Susan Dana

    2014-01-01

    Research anxiety significantly declined in a diverse sample of 59 MSW students in their first-year hybrid online research course in which the instructor used an array of innovative educational techniques empirically proven to reduce this phenomenon. The pretest/posttest study, the standardized survey instruments used, and a summary of these…

  15. Legislation analysis on reducing GHG in Australia

    Institute of Scientific and Technical Information of China (English)

    Yiqi Mao; Li Chen

    2014-01-01

    ‘Greenhouse Effect’ derived from human activities has caused many concerns. This dissertation mainly analysis existing GHG reduction regulations in Australia, the relationship between those regulations, and the effectiveness of the regulatory framework to see whether the CPR Scheme and other complementary strategies can effectively improve the regulatory outcomes, namely reduces GHG emissions.

  16. Reduced-dimension clustering for vegetation segmentation

    NARCIS (Netherlands)

    Steward, B.L.; Tian, L.F.; Nettleton, D.; Tang, L.

    2004-01-01

    Segmentation of vegetation is a critical step in using machine vision for field automation tasks. A new method called reduced-dimensionclustering (RDC) was developed based on theoretical considerations about the color distribution of field images. RDC performed unsupervised classification of pixels

  17. Reducing Alcohol Consumption through Television Advertising.

    Science.gov (United States)

    Barber, James G.; And Others

    1989-01-01

    Assessed impact of television commercial based on controlled-drinking principles. Measures were taken 12 months prior to start of campaign and 3 weeks after campaign from regular drinkers of general public whose drinking behavior was known to be unaffected by previous antidrug advertising campaign. Found that advertisement reduced intake provided…

  18. Detecting reduced renal function in children

    DEFF Research Database (Denmark)

    Andersen, Trine Borup; Jødal, Lars; Erlandsen, Erland J;

    2013-01-01

    Background The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose...

  19. Ways to reduce contamination of foods

    International Nuclear Information System (INIS)

    Radiocesium is one of the most important radionuclides released into the environment. Possibilities of study of reducing the content of radionuclides directly in food have been analysed less. However, a significant reduction of content such as radiocesium we can achieve by leaching, marinating, steeping and cooking to allow in selected foods reach acceptable values. Observation was mainly focused on the mushrooms and meat. (author)

  20. Reduced Component Count RGB LED Driver

    NARCIS (Netherlands)

    De Pedro, I.; Ackermann, B.

    2008-01-01

    The goal of this master thesis is to develop new drive and contrololutions, for creating white light from mixing the light of different-color LEDs, aiming at a reduced component count resulting in less space required by the electronics and lower cost. It evaluates the LED driver concept proposed in

  1. Reduced local energy surface profiles for hydrogen

    International Nuclear Information System (INIS)

    Three dimensional molecular reduced local energy error surface profiles are reported. The calculations are carried out for the hydrogen molecule using the Hartree-Fock wavefunctions of Coulson, Goodisman and Kolos and Roothaan. These surfaces provide both a complete and a simple way to interpret local errors in these wavefunctions. (author)

  2. A reduced volumetric expansion factor plot

    Science.gov (United States)

    Hendricks, R. C.

    1979-01-01

    A reduced volumetric expansion factor plot has been constructed for simple fluids which is suitable for engineering computations in heat transfer. Volumetric expansion factors have been found useful in correlating heat transfer data over a wide range of operating conditions including liquids, gases and the near critical region.

  3. Clinker mineral hydration at reduced relative humidities

    DEFF Research Database (Denmark)

    Jensen, Ole Mejlhede

    1998-01-01

    This report deals with gas phase hydration of pure cement clinker minerals at reduced relative humidities. This is an important subject in relation to modern high performance concrete which may self-desiccate during hydration. In addition the subject has relevance to storage stability where...

  4. Reducing Heating In High-Speed Cinematography

    Science.gov (United States)

    Slater, Howard A.

    1989-01-01

    Infrared-absorbing and infrared-reflecting glass filters simple and effective means for reducing rise in temperature during high-speed motion-picture photography. "Hot-mirror" and "cold-mirror" configurations, employed in projection of images, helps prevent excessive heating of scenes by powerful lamps used in high-speed photography.

  5. Reducing Cholesterol Intake: Are the recommendations valid?

    OpenAIRE

    Chan, Joanna K.; McDonald, Bruce E.

    1991-01-01

    The authors question dietary recommendations for the general public calling for reduced cholesterol intake. Metabolic studies have shown that dietary cholesterol normally induces only small increases in blood cholesterol level. There is evidence that only a portion of the population responds to a change in cholesterol intake; hence lowering dietary cholesterol will be effective for only some.

  6. Reducing methane emissions from ruminant animals

    Energy Technology Data Exchange (ETDEWEB)

    Mathison, G.W.; Okine, E.K.; McAllister, T.A.; Dong, Y.; Galbraith, J.; Dmytruk, O.I.N. [University of Alberta, Edmonton, AB (Canada). Dept. of Agriculture, Food and Nutrition Science

    1998-09-01

    In 1992 it was estimated that 30 x 10{sup 12}g more methane was emitted into the atmosphere than was removed, with animals being considered the largest single anthropogenic source. Ruminants produce 97% of the methane generated in enteric fermentation by animals. Estimates for methane emissions from animal wastes vary between 6 and 31% of that produced directly by the animal, with the most likely value being between 5 and 10% globally. Methane inhibitors can reduce methane emissions to zero in the short term but due to microbial adaptation the effects of these compounds are quickly neutralized and feed intake is often depressed. Methane emissions per unit of feed consumed from sheep and cattle fed hay diets appear to be quite similar but differences between other ruminants have been measured. The most practical way of influencing methane emissions per unit product is to increase productivity level since the proportion of feed energy required to just maintain the animal will be reduced, methane production falls with increased intake level, and the animal may go to market sooner. The most promising avenues for future research for reducing methanogenesis are the development of new products for reducing protozoal numbers in the rumen and the use of bacterocins or other compounds which specifically target methanogenic bacteria.

  7. Reducing the diameters of computer networks

    Science.gov (United States)

    Bokhari, S. H.; Raza, A. D.

    1986-01-01

    Three methods of reducing the diameters of computer networks by adding additional processor to processor links under the constraint that no more than one I/O port be added to each processor are discussed. This is equivalent to adding edges to a given graph under the constraint that the degree of any node be increased, at most, by one.

  8. Reducing Radon in Schools: A Team Approach.

    Science.gov (United States)

    Ligman, Bryan K.; Fisher, Eugene J.

    This document presents the process of radon diagnostics and mitigation in schools to help educators determine the best way to reduce elevated radon levels found in a school. The guidebook is designed to guide school leaders through the process of measuring radon levels, selecting the best mitigation strategy, and directing the efforts of a…

  9. Finding Strategic Solutions to Reduce Truancy

    Science.gov (United States)

    Reid, Ken

    2010-01-01

    This article focuses on recent developments to find strategic solutions to the problem of truancy. It considers issues related to defining truancy and why reducing truancy matters before considering what causes truancy. The article concentrates upon seven areas where further work is needed: the role of parents (and carers); early intervention,…

  10. The status of pathogen-reduced plasma.

    Science.gov (United States)

    Sandler, S Gerald

    2010-12-01

    Efforts to reduce the risk of transfusion-transmitted infectious diseases began more than 4 decades ago with testing donated blood for syphilis. During the subsequent 4 decades, the number of recognized blood-borne transmissible agents and new laboratory tests has proliferated to a logistical breaking point. Further, the number of "emerging agents" which might enter the donor population is increasing continuously. In the search for an alternative to the laboratory testing strategy, pathogen-reduction technologies have emerged as the most promising. The model for this paradigm is pasteurization of a bottle of cow's milk. No matter what infective agent may be present in freshly collected cow's milk, pasteurization, i.e., a generic purification process can eliminate all potential infectivity, while preserving its essential biological properties--and an affordable cost. Several manufacturers have undertaken the challenge of developing a pathogen-reduction technology for blood components. Some novel technologies have proven successful for pooled plasma derivatives such as immune globulins, coagulation factor concentrate concentrates and albumin. The greatest challenge is finding a technology that is suitable for red blood cell and platelet components, whereas significant progress has been made already for pathogen-reduced plasma products. The present review addresses the status of implementation of pathogen-reduced plasma products in the global market. Some blood centers and hospital blood banks in Europe and the Middle East have begun to distribute pathogen-reduced plasma, but no pathogen-reduced plasma product is presently approved by the US Food and Drug Administration. While many observers in the United States focus on the regulatory process as the impediment to widespread implementation, the real challenge will be paying the surcharge for the pathogen-reduction process - an as yet unspecified figure - but likely to add a very substantial amount to the annual

  11. Phenylthiourea specifically reduces zebrafish eye size.

    Directory of Open Access Journals (Sweden)

    Zeran Li

    Full Text Available Phenylthiourea (PTU is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO and sodium-iodide symporter (NIS, suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos.

  12. Human Performance in Simulated Reduced Gravity Environments

    Science.gov (United States)

    Cowley, Matthew; Harvill, Lauren; Rajulu, Sudhakar

    2014-01-01

    NASA is currently designing a new space suit capable of working in deep space and on Mars. Designing a suit is very difficult and often requires trade-offs between performance, cost, mass, and system complexity. Our current understanding of human performance in reduced gravity in a planetary environment (the moon or Mars) is limited to lunar observations, studies from the Apollo program, and recent suit tests conducted at JSC using reduced gravity simulators. This study will look at our most recent reduced gravity simulations performed on the new Active Response Gravity Offload System (ARGOS) compared to the C-9 reduced gravity plane. Methods: Subjects ambulated in reduced gravity analogs to obtain a baseline for human performance. Subjects were tested in lunar gravity (1.6 m/sq s) and Earth gravity (9.8 m/sq s) in shirt-sleeves. Subjects ambulated over ground at prescribed speeds on the ARGOS, but ambulated at a self-selected speed on the C-9 due to time limitations. Subjects on the ARGOS were given over 3 minutes to acclimate to the different conditions before data was collected. Nine healthy subjects were tested in the ARGOS (6 males, 3 females, 79.5 +/- 15.7 kg), while six subjects were tested on the C-9 (6 males, 78.8 +/- 11.2 kg). Data was collected with an optical motion capture system (Vicon, Oxford, UK) and was analyzed using customized analysis scripts in BodyBuilder (Vicon, Oxford, UK) and MATLAB (MathWorks, Natick, MA, USA). Results: In all offloaded conditions, variation between subjects increased compared to 1-g. Kinematics in the ARGOS at lunar gravity resembled earth gravity ambulation more closely than the C-9 ambulation. Toe-off occurred 10% earlier in both reduced gravity environments compared to earth gravity, shortening the stance phase. Likewise, ankle, knee, and hip angles remained consistently flexed and had reduced peaks compared to earth gravity. Ground reaction forces in lunar gravity (normalized to Earth body weight) were 0.4 +/- 0.2 on

  13. Reducing NOx emissions with Group IIIB compounds

    International Nuclear Information System (INIS)

    This patent describes improvement in a process for the catalytic cracking of a heavy hydrocarbon feed containing nitrogen compounds by contact with a circulating inventory of catalytic cracking catalyst to produce catalytically cracked products and spent catalyst containing coke comprising nitrogen compounds. The spent catalyst is regenerated by contact with oxygen or an oxygen-containing gas in a catalyst regeneration zone operating at catalyst regeneration conditions to produce hot regenerated catalyst which is recycled to catalytically crack the heavy feed and the catalyst regeneration zone produces a flue gas comprising CO, CO2 and oxides of nitrogen (NOx). The improvement comprises: reducing the NOx content of the flue gas by adding to the circulating catalyst inventory an additive comprising discrete particles comprising oxides of Group IIIB elements, exclusive of Group III elements which are ion exchanged or impregnated into the cracking catalyst, the additive being added in an amount sufficient to reduce the production of NOx relative to operation without the additive

  14. Behavioral Simulations in MapReduce

    CERN Document Server

    Wang, Guozhang; Sowell, Benjamin; Wang, Xun; Cao, Tuan; Demers, Alan; Gehrke, Johannes; White, Walker

    2010-01-01

    In many scientific domains, researchers are turning to large-scale behavioral simulations to better understand important real-world phenomena. While there has been a great deal of work on simulation tools from the high-performance computing community, behavioral simulations remain challenging to program and automatically scale in parallel environments. In this paper we present BRACE (Big Red Agent-based Computation Engine), which extends the MapReduce framework to process these simulations efficiently across a cluster. We can leverage spatial locality to treat behavioral simulations as iterated spatial joins and greatly reduce the communication between nodes. In our experiments we achieve nearly linear scale-up on several realistic simulations. Though processing behavioral simulations in parallel as iterated spatial joins can be very efficient, it can be much simpler for the domain scientists to program the behavior of a single agent. Furthermore, many simulations include a considerable amount of complex comp...

  15. FETC Programs for Reducing Greenhouse Gas Emissions

    Energy Technology Data Exchange (ETDEWEB)

    Ruether, J.A.

    1998-02-01

    Mark Twain once quipped that everyone talks about the weather but no one does anything about it. With interest in global climate change on the rise, researchers in the fossil-energy sector are feeling the heat to provide new technology to permit continued use of fossil fuels but with reduced emissions of so-called `greenhouse gases.` Three important greenhouse gases, carbon dioxide, methane, and nitrous oxide, are released to the atmosphere in the course of recovering and combusting fossil fuels. Their importance for trapping radiation, called forcing, is in the order given. In this report, we briefly review how greenhouse gases cause forcing and why this has a warming effect on the Earth`s atmosphere. Then we discuss programs underway at FETC that are aimed at reducing emissions of methane and carbon dioxide.

  16. Continuous flash suppression reduces negative afterimages.

    Science.gov (United States)

    Tsuchiya, Naotsugu; Koch, Christof

    2005-08-01

    Illusions that produce perceptual suppression despite constant retinal input are used to manipulate visual consciousness. Here we report on a powerful variant of existing techniques, continuous flash suppression. Distinct images flashed successively at approximately 10 Hz into one eye reliably suppress an image presented to the other eye. The duration of perceptual suppression is at least ten times greater than that produced by binocular rivalry. Using this tool we show that the strength of the negative afterimage of an adaptor was reduced by half when it was perceptually suppressed by input from the other eye. The more completely the adaptor was suppressed, the more strongly the afterimage intensity was reduced. Paradoxically, trial-to-trial visibility of the adaptor did not correlate with the degree of reduction. Our results imply that formation of afterimages involves neuronal structures that access input from both eyes but that do not correspond directly to the neuronal correlates of perceptual awareness. PMID:15995700

  17. Sulfate inhibition effect on sulfate reducing bacteria

    Directory of Open Access Journals (Sweden)

    Sulaiman Al Zuhair

    2008-12-01

    Full Text Available There is an increasing interest in the potential of bacterial sulfate reduction as an alternative method for sulfate removal from wastewater. Under anaerobic conditions, sulfate-reducing bacteria (SRB utilize sulfate to oxidize organic compounds and generate sulfide (S2-. SRB were successfully isolated from sludge samples obtained from a local petroleum refinery, and used for sulfate removal. The effects of initial sulfate concentration, temperature and pH on the rate of bacterial growth and anaerobic sulfate removal were investigated and the optimum conditions were identified. The experimental data were used to determine the parameters of two proposed kinetic model, which take into consideration substrate inhibition effect. Keywords: Sulfate Reducing Bacteria, Sulfate, Kinetic Model, Biotreatement, Inhibition Received: 31 August 2008 / Received in revised form: 18 September 2008, Accepted: 18 September 2008 Published online: 28 September 2008

  18. Reducing stillbirths in low-income countries.

    Science.gov (United States)

    Goldenberg, Robert L; Saleem, Sarah; Pasha, Omrana; Harrison, Margo S; Mcclure, Elizabeth M

    2016-02-01

    Worldwide, 98% of stillbirths occur in low-income countries (LIC), where stillbirth rates are ten-fold higher than in high-income countries (HIC). Although most HIC stillbirths occur prenatally, in LIC most stillbirths occur at term and during labor/delivery. Conditions causing stillbirths include those of maternal origin (obstructed labor, trauma, antepartum hemorrhage, preeclampsia/eclampsia, infection, diabetes, other maternal diseases), and fetal origin (fetal growth restriction, fetal distress, cord prolapse, multiples, malpresentations, congenital anomalies). In LIC, aside from infectious origins, most stillbirths are caused by fetal asphyxia. Stillbirth prevention requires recognition of maternal conditions, and care in a facility where fetal monitoring and expeditious delivery are possible, usually by cesarean section (CS). Of major causes, only syphilis and malaria can be managed prenatally. Targeting single conditions or interventions is unlikely to substantially reduce stillbirth. To reduce stillbirth rates, LIC must implement effective modern antepartum and intrapartum care, including fetal monitoring and CS. PMID:26577070

  19. Brief mindfulness induction reduces inattentional blindness.

    Science.gov (United States)

    Schofield, Timothy P; Creswell, J David; Denson, Thomas F

    2015-12-01

    Prior research has linked mindfulness to improvements in attention, and suggested that the effects of mindfulness are particularly pronounced when individuals are cognitively depleted or stressed. Yet, no studies have tested whether mindfulness improves declarative awareness of unexpected stimuli in goal-directed tasks. Participants (N=794) were either depleted (or not) and subsequently underwent a brief mindfulness induction (or not). They then completed an inattentional blindness task during which an unexpected distractor appeared on the computer monitor. This task was used to assess declarative conscious awareness of the unexpected distractor's presence and the extent to which its perceptual properties were encoded. Mindfulness increased awareness of the unexpected distractor (i.e., reduced rates of inattentional blindness). Contrary to predictions, no mindfulness×depletion interaction emerged. Depletion however, increased perceptual encoding of the distractor. These results suggest that mindfulness may foster awareness of unexpected stimuli (i.e., reduce inattentional blindness).

  20. Reduced accommodation in children with cerebral palsy.

    Science.gov (United States)

    Leat, S J

    1996-09-01

    Accommodation in 43 subjects with cerebral palsy was measured objectively using a dynamic retinoscopy technique, which has already been shown to be reliable and repeatable. The subject's ages ranged from 3 to 35 years. Of these, 42% were found to have an accommodative response pattern which was different from the normal control group for his/her age. Nearly 29% had an estimated amplitude of accommodation of 4 D or less. The presence of reduced accommodation was found to be associated with reduced visual acuity, but was not associated with cognitive or communication ability, refractive error or age. The prevalence of other ocular disorders in this group is also high. These findings have developmental and educational implications.

  1. A New Reducing Regent: Dichloroindium Hydride

    Institute of Scientific and Technical Information of China (English)

    A. BABA; I. SHIBATA; N. HAYASHI

    2005-01-01

    @@ 1Introduction Among the hydride derivatives of group 13 elements, various types of aluminum hydrides and boron hydrides have been employed as powerful reduction tools. Indium hydrides have not received much attention,whereas the synthesis of indium trihydride (InH3) was reported several decades ago[1]. There have been no precedents for monometallic indium hydrides having practical reactivity, while activated hydrides such as an ate complex LiPhn InH4-n (n = 0- 2) and phosphine-coordinated indium hydrides readily reduce carbonyl compounds. In view of this background, we focused on the development of dichloroindium hydrides (Cl2InH) as novel reducing agents that bear characteristic features in both ionic and radical reactions.

  2. ECONOMIC GROWTH AND EQUALITY IN REDUCING POVERTY

    Directory of Open Access Journals (Sweden)

    Zaenal Muttaqin

    2016-02-01

    Full Text Available In some developing countries, the instrument to alleviate the poverty is by using the economic growth. So, the increasing in investment, infrastructure development, and macroeconomics stability always be priority from developing countries. In this article explain that economic growth is not the important factor to alleviate the poverty, because equality sometimes is more important rather than the economic growth. In this context, its measure by inequality growth trade off index (IGTI. This method is to measure the influence of economic growth to reducing the inequality, with this method every country can measure which one is better to reducing the poverty whether the economic growth or equality. With this method, Laos in 2000 show that economic growth is more important than equality, but in the same year in Thailand show that equality is more important than economic growth.DOI: 10.15408/sjie.v1i1.2592

  3. COMPUTER SIMULATION SYSTEM OF STRETCH REDUCING MILL

    Institute of Scientific and Technical Information of China (English)

    B.Y. Sun; S.J. Yuan

    2007-01-01

    The principle of the stretch reducing process is analyzed and three models of pass design areestablished. The simulations are done about variables, such as, stress, strain, the stretches betweenthe stands, the size parameters of the steel tube, and the roll force parameters. According to itsproduct catalogs the system can automatically divide the pass series, formulate the rolling table,and simulate the basic technological parameters in the stretch reducing process. All modules areintegrated based on the developing environment of VB6. The system can draw simulation curvesand pass pictures. Three kinds of database including the material database, pass design database,and product database are devised using Microsoft Access, which can be directly edited, corrected,and searched.

  4. Gratitude: a tool for reducing economic impatience.

    Science.gov (United States)

    DeSteno, David; Li, Ye; Dickens, Leah; Lerner, Jennifer S

    2014-06-01

    The human mind tends to excessively discount the value of delayed rewards relative to immediate ones, and it is thought that "hot" affective processes drive desires for short-term gratification. Supporting this view, recent findings demonstrate that sadness exacerbates financial impatience even when the sadness is unrelated to the economic decision at hand. Such findings might reinforce the view that emotions must always be suppressed to combat impatience. But if emotions serve adaptive functions, then certain emotions might be capable of reducing excessive impatience for delayed rewards. We found evidence supporting this alternative view. Specifically, we found that (a) the emotion gratitude reduces impatience even when real money is at stake, and (b) the effects of gratitude are differentiable from those of the more general positive state of happiness. These findings challenge the view that individuals must tamp down affective responses through effortful self-regulation to reach more patient and adaptive economic decisions. PMID:24760144

  5. Costs of reducing nutrient losses in Denmark

    DEFF Research Database (Denmark)

    Jacobsen, Brian H.; Abildtrup, Jens; Jensen, Jørgen Dejgård;

    The economic calculations carried out prior to the Plan for the Aquatic Environment III included a comparison of regulation systems aimed at reducing nitrogen leaching, analyses of measures for reducing phosphorus losses and estimation of administrative costs. The conclusions were that taxation...... of the N-surplus introduced at the sector level was the most cost effective regulation when compared with administrative regulation and set a side. For phosphorus a balance between incoming and outgoing phosphorus is very costly as this requires that much slurry is transported from the western...... to the eastern part of Denmark. The final plan for the Aquatic Environment III from 2004 included a 13% reduction of N-leaching until 2015 based on cost effective administrative measures like wetlands and catch crops. Also a tax on mineral phosphorus in feedstuffs was included in order to half the phosphorus...

  6. Advanced technology development reducing CO2 emissions

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Sup

    2010-09-15

    Responding to Korean government policies on green growth and global energy/ environmental challenges, SK energy has been developing new technologies to reduce CO2 emissions by 1) CO2 capture and utilization, 2) efficiency improvement, and 3) Li-ion batteries. The paper introduces three advanced technologies developed by SK energy; GreenPol, ACO, and Li-ion battery. Contributing to company vision, a more energy and less CO2, the three technologies are characterized as follows. GreenPol utilizes CO2 as a feedstock for making polymer. Advanced Catalytic Olefin (ACO) reduces CO2 emission by 20% and increase olefin production by 17%. Li-ion Batteries for automotive industries improves CO2 emission.

  7. Activity of Reducing Steel Slag of EAF

    Institute of Scientific and Technical Information of China (English)

    GUO Chinhsiang; HWANG Chaolung; LIN Tingyi

    2011-01-01

    Reducing steel slag (RSS) was mainly acquired from five electric-arc furnace (EAF)steelmaking plants (among them, the products of two plants were carbon steel and those of other plants were stainless steel) for research tests. The chemical properties, compound compositions, activities and contents of main expansive compounds were tested. The results showed that the field sampled RSS had a very high crystallinity and hydraulicity with main chemical compositions close to those of Portland cement. It can be known from the study that in case of C/S ratio higher than 2.0, the main compound compositions are C2S, C3S, C2F and f-CaO. However, after the RSS was stored for six months, an obvious variation occurred with potential pre-hydration in RSS, where the SO3 content was slightly reduced and the compressive activity index was obviously higher than that at the 28th day.

  8. Reduced TCA Flux in Diabetic Myotubes

    DEFF Research Database (Denmark)

    Gaster, Michael

    2012-01-01

    production in isolated mitochondria from substrates entering the TCA cycle at various points. ATP production was measured by luminescence with or without concomitant ATP utilisation by hexokinase in mitochondria isolated from myotubes established from eight lean and eight type 2 diabetic subjects. The ATP...... production of investigated substrate combinations was significantly reduced in mitochondria isolated from type 2 diabetic subjects compared to lean. However, when ATP synthesis rates at different substrate combinations were normalized to the corresponding individual pyruvate-malate rate, there was no......The diabetic phenotype is complex, requiring elucidation of key initiating defects. Diabetic myotubes express a primary reduced tricarboxylic acid (TCA) cycle flux but at present it is unclear in which part of the TCA cycle the defect is localised. In order to localise the defect we studied ATP...

  9. Reduced central blood volume in cirrhosis

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Bendtsen, Flemming; Sørensen, T I;

    1989-01-01

    was inversely correlated to the systemic vascular resistance (r = -0.49, p less than 0.001), the latter being significantly reduced in the patient group. Patients with cirrhosis apparently are unable to maintain a normal central blood volume. This may be due to arteriolar vasodilation, portosystemic collateral......The pathogenesis of ascites formation in cirrhosis is uncertain. It is still under debate whether the effective blood volume is reduced (underfilling theory) or whether the intravascular compartment is expanded (overflow theory). This problem has not yet been solved because of insufficient tools...... for measuring the central blood volume. We have developed a method that enables us to determine directly the central blood volume, i.e., the blood volume in the heart cavities, lungs, and central arterial tree. In 60 patients with cirrhosis and 16 control subjects the central blood volume was assessed according...

  10. Methods of reducing vehicle aerodynamic drag

    Energy Technology Data Exchange (ETDEWEB)

    Sirenko V.; Rohatgi U.

    2012-07-08

    A small scale model (length 1710 mm) of General Motor SUV was built and tested in the wind tunnel for expected wind conditions and road clearance. Two passive devices, rear screen which is plate behind the car and rear fairing where the end of the car is aerodynamically extended, were incorporated in the model and tested in the wind tunnel for different wind conditions. The conclusion is that rear screen could reduce drag up to 6.5% and rear fairing can reduce the drag by 26%. There were additional tests for front edging and rear vortex generators. The results for drag reduction were mixed. It should be noted that there are aesthetic and practical considerations that may allow only partial implementation of these or any drag reduction options.

  11. Designing reduced beacon trajectory for sensor localization

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Localization is one of the substantial issues in wireless sensor networks. The key problem for the mobile beacon localization is how to choose the appropriate beacon trajectory. However, little research has been done on it. In this paper, firstly,we deduce the number of positions for a beacon to send a packet according to the acreage of ROI (region of interest); and next we present a novel method based on virtual force to arrange the positions in arbitrary ROI; then we apply TSP (travelling salesman problem) algorithm to the positions sequence to obtain the optimal touring path, i.e. the reduced beacon trajectory. When a mobile beacon moves along the touring path, sending RF signals at every position, the sensors in ROI can work out their position with trilateration. Experimental results demonstrate that the localization method, based on the beacon reduced path, is efficient and has flexible accuracy.

  12. Climatology: Contrails reduce daily temperature range

    Science.gov (United States)

    Travis, David J.; Carleton, Andrew M.; Lauritsen, Ryan G.

    2002-08-01

    The potential of condensation trails (contrails) from jet aircraft to affect regional-scale surface temperatures has been debated for years, but was difficult to verify until an opportunity arose as a result of the three-day grounding of all commercial aircraft in the United States in the aftermath of the terrorist attacks on 11 September 2001. Here we show that there was an anomalous increase in the average diurnal temperature range (that is, the difference between the daytime maximum and night-time minimum temperatures) for the period 11-14 September 2001. Because persisting contrails can reduce the transfer of both incoming solar and outgoing infrared radiation and so reduce the daily temperature range, we attribute at least a portion of this anomaly to the absence of contrails over this period.

  13. Evolution of technetium speciation in reducing grout.

    Science.gov (United States)

    Lukens, Wayne W; Bucher, Jerome I; Shuh, David K; Edelstein, Norman M

    2005-10-15

    Cementitious waste forms (CWFs) are an important component of the strategy to stabilize nuclear waste resulting from plutonium production by the U. S. Department of Energy. Technetium (99Tc) is an abundant fission product of particular concern in CWFs because of the high solubility and mobility of Tc(VII), pertechnetate (TcO4-), the stable form of technetium in aerobic environments. CWFs can more effectively stabilize 99Tc if they contain additives that chemically reduce mobile TcO4- to immobile Tc(IV) species. The 99Tc leach rate of reducing CWFs that contain Tc(IV) is much lower than that for CWFs that contain TcO4-. Previous X-ray absorption fine structure studies showed that Tc(IV) species were oxidized to TcO4- in reducing grout samples prepared on a laboratory scale. Whether the oxidizer was atmospheric O2 or NO3- in the waste simulant was not determined. In actual CWFs, rapid oxidation of Tc(IV) by NO3- would be of concern, whereas oxidation by atmospheric O2 would be of less concern due to the slow diffusion and reaction of O2 with the reducing CWF. To address this uncertainty, two series of reducing grouts were prepared using TcO4- containing waste simulants with and without NO3-. In the first series of samples, referred to as "permeable samples", the TcO4- was completely reduced using Na2S, and the samples were sealed in cuvettes made of polystyrene, which has a relatively large O2 diffusion coefficient. In these samples, all of the technetium was initially present as a Tc(IV) sulfide compound, TcSx, which was characterized by extended X-ray absorption fine structure (EXAFS) spectroscopy. The EXAFS data is consistent with a structure consisting of triangular clusters of Tc(IV) centers linked together through a combination of disulfide and sulfide bridges as in MoS3. From the EXAFS model, the stoichiometry of TcSx is TC3S10, which is presumably the compound generally referred to as "Tc2S7". The TcSX initially present in the permeable samples was steadily

  14. Deciding for Others Reduces Loss Aversion

    DEFF Research Database (Denmark)

    Andersson, Ola; Holm, Håkan J.; Tyran, Jean-Robert Karl;

    2014-01-01

    We study risk taking on behalf of others, both when choices involve losses and when they do not. A large-scale incentivized experiment with subjects randomly drawn from the Danish population is conducted. We find that deciding for others reduces loss aversion. When choosing between risky prospect...... others when losses loom. This finding is consistent with an interpretation of loss aversion as a bias in decision making driven by emotions and that these emotions are reduced when making decisions for others....... for which losses are ruled out by design, subjects make the same choices for themselves as for others. In contrast, when losses are possible, we find that the two types of choices differ. In particular, we find that subjects who make choices for themselves take less risk than those who decide for...

  15. Activating Attachments Reduces Memories of Traumatic Images.

    Science.gov (United States)

    Bryant, Richard A; Foord, Rachael

    2016-01-01

    Emotional memories, and especially intrusive memories, are a common feature of many psychological disorders, and are overconsolidated by stress. Attachment theory posits that activation of mental representations of attachment figures can reduce stress and boost coping. This study tested the proposition that attachment activation would reduce consolidation of emotional and intrusive memories. Sixty-seven undergraduate students viewed subliminal presentations of traumatic and neutral images, which were preceded by subliminal presentations of either attachment-related images or non-attachment-related images; free recall and intrusive memories were assessed two days later. Participants with low avoidant attachment tendencies who received the attachment primes recalled fewer memories and reported fewer intrusions than those who received the non-attachment primes. Unexpectedly, those with high anxious attachment tendencies reported fewer memories. These findings generally accord with attachment theory, and suggest that consolidation of emotional memories can be moderated by activation of attachment representations. PMID:27631498

  16. Metabolic Flexibility of Sulfate-Reducing Bacteria

    OpenAIRE

    Plugge, Caroline M.; Zhang, Weiwen; Scholten, Johannes C. M.; Stams, Alfons J. M.

    2011-01-01

    Dissimilatory sulfate-reducing prokaryotes (SRB) are a very diverse group of anaerobic bacteria that are omnipresent in nature and play an imperative role in the global cycling of carbon and sulfur. In anoxic marine sediments sulfate reduction accounts for up to 50% of the entire organic mineralization in coastal and shelf ecosystems where sulfate diffuses several meters deep into the sediment. As a consequence, SRB would be expected in the sulfate-containing upper sediment layers, whereas me...

  17. Reducing stigma and discrimination: Candidate interventions

    OpenAIRE

    Kassam Aliya; Brohan Elaine; Thornicroft Graham; Lewis-Holmes Elanor

    2008-01-01

    Abstract This paper proposes that stigma in relation to people with mental illness can be understood as a combination of problems of knowledge (ignorance), attitudes (prejudice) and behaviour (discrimination). From a literature review, a series of candidate interventions are identified which may be effective in reducing stigmatisation and discrimination at the following levels: individuals with mental illness and their family members; the workplace; and local, national and international. The ...

  18. BF topological theories and infinitely reducible systems

    CERN Document Server

    Caicedo, M I; Bol, S; Bol, Simon

    1996-01-01

    We present a rigurous disscusion for abelian BF theories in which the base manifold of the U(1) bundle is homeomorphic to a Hilbert space. The theory has an infinte number of stages of reducibility. We specify conditions on the base manifold under which the covarinat quantization of the system can be performed unambiguously. Applications of the formulation to the superparticle and the supertstring are also discussed.

  19. Leveraging Technology to Reduce Patient Transaction Costs.

    Science.gov (United States)

    Edlow, Richard C

    2015-01-01

    Medical practices are under significant pressure to provide superior customer service in an environment of declining or flat reimbursement. The solution for many practices involves the integration of a variety of third-party technologies that conveniently interface with one's electronic practice management and medical records systems. Typically, the applications allow the practice to reduce the cost of each patient interaction. Drilling down to quantify the cost of each individual patient interaction helps to determine the practicality of implementation. PMID:26665478

  20. Role of Insurance in Reducing Flood Risk

    OpenAIRE

    David Crichton

    2008-01-01

    This paper considers the problems of flood risk management in the context of public and private insurance. It demonstrates the important role of insurance in reducing flood risk with examples from the U.K. and France. It includes a brief description of the summer 2007 floods in England. The Geneva Papers (2008) 33, 117–132. doi:10.1057/palgrave.gpp.2510151

  1. Reducing mother-to-child HIV transmission

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In developing countries,mother-to-child trans mission of human immune deficiency virus (HIV)is responsible for 5 to 10 percen t o f all new HIV infections.Most children born to HIV-positive mothers are not HIV positive,but one quarter to one third are.The following instert looks at the p o ssibilities for reducing mother-to-child HIV transmission,and discusses some of the questions that are still unanswered.

  2. Testosterone therapy for reduced libido in women

    OpenAIRE

    Basson, Rosemary

    2010-01-01

    Modest benefit has been shown from transdermal testosterone therapy given to postmenopausal women with reduced sexual desire. An increased frequency of satisfying sexual encounters and intensity of sexual desire and response has been shown in medically and psychiatrically healthy women able to have 2–3 satisfying sexual experiences each month before therapy commences. Women more clearly sexually dysfunctional in keeping with currently proposed definitions of sexual disorder have not been stud...

  3. Incentives for reducing emissions in Krakow

    International Nuclear Information System (INIS)

    This effort is identifying, specific incentives that may be used by Krakow city officials to encourage, residents to change the way they heat their homes and businesses in order to reduce pollution. This paper describes the incentives study for converting small coal or coke-fired boilers to gas in the Old Town area. A similar study looked at incentives for expanding the district heating system and future analyses will be performed for home stove options

  4. Improved regularization from Quantum Reduced Loop Gravity

    CERN Document Server

    Alesci, Emanuele

    2016-01-01

    The choice of the regularization scheme in Loop Quantum Cosmology (LQC) is crucial for the predicted phenomenology. We outline how the improved scheme can be naturally realized in Quantum Reduced Loop Gravity, describing the Universe as an ensemble of microstates labeled by different graphs. The new effective dynamics presents corrections to LQC, which do not significantly affect the bouncing scenario for the most relevant kinds of matter fields in cosmology $(w \\leq 1)$.

  5. Reducing murder to manslaughter: whose job?

    OpenAIRE

    Griew, E

    1986-01-01

    This paper compares two versions of the diminished responsibility defence, which reduces murder to manslaughter: the present statutory formulation and a proposed reformulation. The comparison confirms that evidence such as psychiatrists are commonly invited to give in murder cases takes them beyond their proper role. Paradoxically, although the two formulations mean essentially the same thing, the proposed change of wording must have the practical effect of subduing the psychiatrist's evidenc...

  6. Nonuniform Banking for Reducing Memory Energy Consumption

    OpenAIRE

    Ozturk, Ozcan; Kandemir, Mahmut

    2005-01-01

    Submitted on behalf of EDAA (http://www.edaa.com/) International audience Main memories can consume a large percentage of overall energy in many data-intensive embedded applications. The past research proposed and evaluated memory banking as a possible approach for reducing memory energy consumption. One of the common characteristics/assumptions made by most of the past work on banking is that all the banks are of the same size. While this makes the formulation of the problem easy, it a...

  7. Thermosyphon Flooding in Reduced Gravity Environments

    Science.gov (United States)

    Gibson, Marc Andrew

    2013-01-01

    An innovative experiment to study the thermosyphon flooding limits was designed and flown on aparabolic flight campaign to achieve the Reduced Gravity Environments (RGE) needed to obtainempirical data for analysis. Current correlation models of Faghri and Tien and Chung do not agreewith the data. A new model is presented that predicts the flooding limits for thermosyphons inearths gravity and lunar gravity with a 95 confidence level of +- 5W.

  8. Forewarning reduces fraud susceptibility in vulnerable consumers

    OpenAIRE

    Scheibe, Susanne; Notthoff, Nanna; Menkin, Josephine; Ross, Lee; Shadel, Doug; Deevy, Martha; Carstensen, Laura L.

    2014-01-01

    Telemarketing fraud is pervasive and older consumers are disproportionally targeted. Given laboratory research showing that forewarning can effectively counter influence appeals, we conducted a field experiment to test whether forewarning could protect people who had been victimized in the past. A research assistant with prior experience as a telemarketer pitched a mock scam two or four weeks after participants were warned about the same scam or an entirely different scam. Both warnings reduc...

  9. Reducing the surface deviation of stereolithography components

    OpenAIRE

    Reeves, Philip E.

    1998-01-01

    The Stereolithography (SL) process has developed into an accurate method of replicating 3D CAD images into tactile objects used for functions such as product evaluation, preproduction testing or as patterns around which tool cavities can be formed. One of the main limitations with the SL process is the surface roughness of parts resulting from the layer manufacturing process. To-date surface roughness has only been reduced using techniques such as additive coating or abrasive finishing. Resea...

  10. Reduced Palm Intensity for Track Extraction

    OpenAIRE

    Bozdogan, Ali Onder; Streit, Roy; EFE, Murat

    2015-01-01

    The pair correlation function is introduced to target tracking filters that use a finite point process target model as a means to investigate interactions in the Bayes posterior target process. It is shown that the Bayes posterior target point process of the probability hypothesis density (PHD) filter-before using the Poisson point process approximation to close the recursion-is a spatially correlated process with weakly repulsive pair interactions. The reduced Palm target point process is in...

  11. Phenelzine reduces plasma vitamin B6.

    OpenAIRE

    Malcolm, D E; Yu, P H; Bowen, R.C.; O'Donovan, C.; Hawkes, J; Hussein, M

    1994-01-01

    Plasma levels of the active form of vitamin B6 (pyridoxal phosphate) in 19 patients taking phenelzine were found to be reduced on the average to approximately 54% of the value in a control group. There was no correlation of pyridoxal phosphate level with phenelzine daily dosage over the range of 30 mg to 90 mg. No symptoms of vitamin B6 deficiency peripheral neuropathy were found.

  12. Quantum-Reduced Loop Gravity: Cosmology

    OpenAIRE

    Alesci, Emanuele; Cianfrani, Francesco

    2013-01-01

    We introduce a new framework for loop quantum gravity: mimicking the spinfoam quantization procedure we propose to study the symmetric sectors of the theory imposing the reduction weakly on the full kinematical Hilbert space of the canonical theory. As a first application of Quantum-Reduced Loop Gravity we study the inhomogeneous Bianchi I model. The emerging quantum cosmological model represents a simplified arena on which the complete canonical quantization program can be tested. The achiev...

  13. Reduced energy conservation law for magnetized plasma

    International Nuclear Information System (INIS)

    A global energy conservation law for a magnetized plasma is studied within the context of a quasiparticle description. A reduced energy conservation law is derived for low-frequency, as compared to the gyromagnetic frequency, plasma motions with regard to both non-uniform mean flows and fluctuations in the plasma. The mean value of plasma energy is calculated and sufficient stability conditions for non-equilibrium plasmas are derived. (orig.)

  14. Reduce Demand Rather than Increase Supply

    OpenAIRE

    Shoup, Donald C.

    2006-01-01

    The logic behind off-street parking requirements is simple: development increases the demand for parking, so cities require enough off-street spaces to satisfy this new demand. Off-street parking requirements thus ensure that cars will not spill over onto the neighborhood streets. This logic suggests another potential reform within the existing system of off-street parking requirements: if developers reduce parking demand, cities should allow them to provide fewer parking spaces; that is, cit...

  15. Personalized music to reduce patient anxiety (abstract)

    OpenAIRE

    Zwaag, M. van der; Tijs, T.J.W.; Westerink, J.H.D.

    2012-01-01

    Patient anxiety is a frequently occurring concern as it decreases patient satisfaction, increases consultation duration, and can influence successful medical outcome. To illustrate, for some diagnosis methods as PET scans patients need to be relaxed for successful medicaloutcome. Music can possibly reduce patients stress. However, hospital selected music has not always shown its effectiveness, and patient selected music has shown it could be arousing instead of relaxing.In two experiments the...

  16. Reducing ICT project failure with scope management

    OpenAIRE

    Acquah, Ato

    2011-01-01

    Over the years, Information Communications and Technology projects have had a high rate of failure according to previous research findings. The aim of this thesis is to investigate the various factors causing project failure and to show how the problem can be eliminated or reduced by effectively managing the scope of projects. The research approach used was a qualitative method with an empirical investigation. The thesis was divided into two parts, the Theoretical part and Empirical p...

  17. Causal transmission in reduced-form models

    OpenAIRE

    Vassili Bazinas; Bent Nielsen

    2015-01-01

    We propose a method to explore the causal transmission of a catalyst variable through two endogenous variables of interest. The method is based on the reduced-form system formed from the conditional distribution of the two endogenous variables given the catalyst. The method combines elements from instru- mental variable analysis and Cholesky decomposition of structural vector autoregressions. We give conditions for uniqueness of the causal transmission.

  18. Whole Grain Intake Reduces Pancreatic Cancer Risk

    OpenAIRE

    Lei, Qiucheng; Zheng, Huazhen; Bi, Jingcheng; Wang, Xinying; Jiang, Tingting; Gao, Xuejin; Tian, Feng; Xu, Min; Wu, Chao; Zhang, Li; Ning LI; Li, Jieshou

    2016-01-01

    Abstract Mounting evidence from epidemiology studies suggests that whole grain intake may reduce pancreatic cancer risk, but convincing evidence is scarce. We conducted a meta-analysis to assess the association between whole grain intake and pancreatic cancer risk. Relevant observational studies were identified by searching PubMed, Embase, Scopus, and Cochrane library databases for the period from January 1980 to July 2015, with no restrictions. We calculated the summary odds ratios (ORs) for...

  19. Reducing hazards for animals from humans

    OpenAIRE

    Paul-Pierre Pastoret

    2012-01-01

    If animals may be a source of hazards for humans, the reverse is equally true. The main sources of hazards from humans to animals, are the impact of human introduction of transboundary animal diseases, climate change, globalisation, introduction of invasive species and reduction of biodiversity.There is also a trend toward reducing genetic diversity in domestic animals, such as cattle; there are presently around 700 different breeds of cattle many of which at the verge of extinction (less tha...

  20. European Community Measures to Reduce Nitrate Pollution

    OpenAIRE

    Al-hedny, Suhad

    2010-01-01

    Water protection proves to be a difficult task, whether it is dealt with through legislation or the implementation of a process to reduce further pollution. This study considers how the issue of water pollution from nitrates in agricultural practices has become better understood through the reforms of the common agriculture policy (CAP) and the enactment of various regulations and directives by EU. The implementation of the EC Nitrate Directive is a main focus of this study because it was a m...

  1. Reducing or enhancing chaos using periodic orbits.

    Science.gov (United States)

    Bachelard, R; Chandre, C; Leoncini, X

    2006-06-01

    A method to reduce or enhance chaos in Hamiltonian flows with two degrees of freedom is discussed. This method is based on finding a suitable perturbation of the system such that the stability of a set of periodic orbits changes (local bifurcations). Depending on the values of the residues, reflecting their linear stability properties, a set of invariant tori is destroyed or created in the neighborhood of the chosen periodic orbits. An application on a paradigmatic system, a forced pendulum, illustrates the method.

  2. Swimming Motility Reduces Deposition to Silica Surfaces

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Nanxi [Univ. of Illinois, Urbana-Champaign, IL (United States); Massoudieh, Arash [The Catholic Univ. of America, Washington, DC (United States); Liang, Xiaomeng [The Catholic Univ. of America, Washington, DC (United States); Hu, Dehong [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kamai, Tamir [Agricultural Research Organization, Bet Dagan (Israel); Ginn, Timothy R. [Univ. of California, Davis, CA (United States); Zilles, Julie L. [Univ. of Illinois, Urbana-Champaign, IL (United States); Nguyen, Thanh H. [Univ. of Illinois, Urbana-Champaign, IL (United States)

    2015-01-01

    The role of swimming motility on bacterial transport and fate in porous media was evaluated. We present microscopic evidence showing that strong swimming motility reduces attachment of Azotobacter vinelandii cells to silica surfaces. Applying global and cluster statistical analyses to microscopic videos taken under non-flow conditions, wild type, flagellated A. vinelandii strain DJ showed strong swimming ability with an average speed of 13.1 μm/s, DJ77 showed impaired swimming averaged at 8.7 μm/s, and both the non-flagellated JZ52 and chemically treated DJ cells were non-motile. Quantitative analyses of trajectories observed at different distances above the collector of a radial stagnation point flow cell (RSPF) revealed that both swimming and non-swimming cells moved with the flow when at a distance of at least 20 μm from the collector surface. Near the surface, DJ cells showed both horizontal and vertical movement diverging them from reaching surfaces, while chemically treated DJ cells moved with the flow to reach surfaces, suggesting that strong swimming reduced attachment. In agreement with the RSPF results, the deposition rates obtained for two-dimensional multiple-collector micromodels were also lowest for DJ, while DJ77 and JZ52 showed similar values. Strong swimming specifically reduced deposition on the upstream surfaces of the micromodel collectors.

  3. Monitoring sulfide and sulfate-reducing bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Tanner, R.S.

    1995-12-31

    Simple yet precise and accurate methods for monitoring sulfate-reducing bacteria (SRB) and sulfide remain useful for the study of bacterial souring and corrosion. Test kits are available to measure sulfide in field samples. A more precise methylene blue sulfide assay for both field and laboratory studies is described here. Improved media, compared to that in API RP-38, for enumeration of SRB have been formulated. One of these, API-RST, contained cysteine (1.1 mM) as a reducing agent, which may be a confounding source of sulfide. While cysteine was required for rapid enumeration of SRB from environmental samples, the concentration of cysteine in medium could be reduced to 0.4 mM. It was also determined that elevated levels of yeast extract (>1 g/liter) could interfere with enumeration of SRB from environmental samples. The API-RST medium was modified to a RST-11 medium. Other changes in medium composition, in addition to reduction of cysteine, included reduction of the concentration of phosphate from 3.4 mM to 2.2 mM, reduction of the concentration of ferrous iron from 0.8 mM to 0.5 mM and preparation of a stock mineral solution to ease medium preparation. SRB from environmental samples could be enumerated in a week in this medium.

  4. Reduced barrier efficiency in axillary stratum corneum.

    Science.gov (United States)

    Watkinson, A; Lee, R S; Moore, A E; Pudney, P D A; Paterson, S E; Rawlings, A V

    2002-06-01

    The skin of the axilla is cosmetically important with millions of consumers daily applying antiperspirant/deodorant products. Despite this, we know virtually nothing about axillary skin or how antiperspirant (AP) use impacts upon it. To characterize the axillary stratum corneum and determine whether this is a unique skin type, we have looked at stratum corneum composition and function, particularly its barrier properties, and compared it with other body sites. Transepidermal water loss (TEWL) and corneosurfametry (CSM) revealed a reduced barrier function in the axilla. HPTLC analysis of the stratum corneum lipids demonstrated statistically elevated levels of fatty acids, ceramides, and particularly cholesterol in the axilla. Both ceramide and cholesterol did not appear to change with depth, indicating that they were predominantly of stratum corneum origin. On the other hand, at least some of the fatty acid had a sebaceous origin. We hypothesized that the reduced barrier function might be owing to the changes in the crucial ceramide : cholesterol ratio. To address this, we used a combination of attenuated total reflectance-Fourier-transformed infrared spectroscopy (ATR-FTIR) with cyanoacrylate sampling. These results demonstrated more ordered lipid-lamellae phase behaviour in the axilla, suggesting that the elevated cholesterol might form crystal microdomains within the lipid lamellae, allowing an increase in water flux. Since an exaggerated application of antiperspirant had no effect upon the axilla barrier properties, it is concluded that this region of skin physiologically has a reduced barrier function.

  5. Fungal Aflatoxins Reduce Respiratory Mucosal Ciliary Function.

    Science.gov (United States)

    Lee, Robert J; Workman, Alan D; Carey, Ryan M; Chen, Bei; Rosen, Phillip L; Doghramji, Laurel; Adappa, Nithin D; Palmer, James N; Kennedy, David W; Cohen, Noam A

    2016-01-01

    Aflatoxins are mycotoxins secreted by Aspergillus flavus, which can colonize the respiratory tract and cause fungal rhinosinusitis or bronchopulmonary aspergillosis. A. flavus is the second leading cause of invasive aspergillosis worldwide. Because many respiratory pathogens secrete toxins to impair mucociliary immunity, we examined the effects of acute exposure to aflatoxins on airway cell physiology. Using air-liquid interface cultures of primary human sinonasal and bronchial cells, we imaged ciliary beat frequency (CBF), intracellular calcium, and nitric oxide (NO). Exposure to aflatoxins (0.1 to 10 μM; 5 to 10 minutes) reduced baseline (~6-12%) and agonist-stimulated CBF. Conditioned media (CM) from A. fumigatus, A. niger, and A. flavus cultures also reduced CBF by ~10% after 60 min exposure, but effects were blocked by an anti-aflatoxin antibody only with A. flavus CM. CBF reduction required protein kinase C but was not associated with changes in calcium or NO. However, AFB2 reduced NO production by ~50% during stimulation of the ciliary-localized T2R38 receptor. Using a fluorescent reporter construct expressed in A549 cells, we directly observed activation of PKC activity by AFB2. Aflatoxins secreted by respiratory A. flavus may impair motile and chemosensory functions of airway cilia, contributing to pathogenesis of fungal airway diseases. PMID:27623953

  6. Reduced particle settling speed in turbulence

    CERN Document Server

    Fornari, Walter; Sardina, Gaetano; Brandt, Luca

    2016-01-01

    We study the settling of finite-size rigid spheres in sustained homogeneous isotropic turbulence (HIT) using Direct Numerical Simulations. In particular, an immersed boundary method is used to account for the dispersed solid phase. We study semi-dilute suspensions of spheres at different Galileo numbers, Ga. The Galileo number is the ratio between buoyancy and viscous forces, and is here varied via the solid-to-fluid density ratio. The focus is on particles that are slightly heavier than the fluid. We find that in HIT, the mean settling speed is less than in quiescent fluid and it reduces by 6 to 60\\% with respect to the terminal velocity of an isolated sphere in quiescent fluid "Vt", as the ratio between "Vt" and the turbulent velocity fluctuations u' is decreased. Analysing the fluid-particle relative motion, we find that the mean settling speed is progressively reduced while reducing due to the increase of the vertical drag induced by the particle cross-flow velocity. Unsteady effects contribute to the mea...

  7. Analytic thinking reduces belief in conspiracy theories.

    Science.gov (United States)

    Swami, Viren; Voracek, Martin; Stieger, Stefan; Tran, Ulrich S; Furnham, Adrian

    2014-12-01

    Belief in conspiracy theories has been associated with a range of negative health, civic, and social outcomes, requiring reliable methods of reducing such belief. Thinking dispositions have been highlighted as one possible factor associated with belief in conspiracy theories, but actual relationships have only been infrequently studied. In Study 1, we examined associations between belief in conspiracy theories and a range of measures of thinking dispositions in a British sample (N=990). Results indicated that a stronger belief in conspiracy theories was significantly associated with lower analytic thinking and open-mindedness and greater intuitive thinking. In Studies 2-4, we examined the causational role played by analytic thinking in relation to conspiracist ideation. In Study 2 (N=112), we showed that a verbal fluency task that elicited analytic thinking reduced belief in conspiracy theories. In Study 3 (N=189), we found that an alternative method of eliciting analytic thinking, which related to cognitive disfluency, was effective at reducing conspiracist ideation in a student sample. In Study 4, we replicated the results of Study 3 among a general population sample (N=140) in relation to generic conspiracist ideation and belief in conspiracy theories about the July 7, 2005, bombings in London. Our results highlight the potential utility of supporting attempts to promote analytic thinking as a means of countering the widespread acceptance of conspiracy theories.

  8. Analytic thinking reduces belief in conspiracy theories.

    Science.gov (United States)

    Swami, Viren; Voracek, Martin; Stieger, Stefan; Tran, Ulrich S; Furnham, Adrian

    2014-12-01

    Belief in conspiracy theories has been associated with a range of negative health, civic, and social outcomes, requiring reliable methods of reducing such belief. Thinking dispositions have been highlighted as one possible factor associated with belief in conspiracy theories, but actual relationships have only been infrequently studied. In Study 1, we examined associations between belief in conspiracy theories and a range of measures of thinking dispositions in a British sample (N=990). Results indicated that a stronger belief in conspiracy theories was significantly associated with lower analytic thinking and open-mindedness and greater intuitive thinking. In Studies 2-4, we examined the causational role played by analytic thinking in relation to conspiracist ideation. In Study 2 (N=112), we showed that a verbal fluency task that elicited analytic thinking reduced belief in conspiracy theories. In Study 3 (N=189), we found that an alternative method of eliciting analytic thinking, which related to cognitive disfluency, was effective at reducing conspiracist ideation in a student sample. In Study 4, we replicated the results of Study 3 among a general population sample (N=140) in relation to generic conspiracist ideation and belief in conspiracy theories about the July 7, 2005, bombings in London. Our results highlight the potential utility of supporting attempts to promote analytic thinking as a means of countering the widespread acceptance of conspiracy theories. PMID:25217762

  9. Does Metformin Reduce Cancer Risks? Methodologic Considerations.

    Science.gov (United States)

    Golozar, Asieh; Liu, Shuiqing; Lin, Joeseph A; Peairs, Kimberly; Yeh, Hsin-Chieh

    2016-01-01

    The substantial burden of cancer and diabetes and the association between the two conditions has been a motivation for researchers to look for targeted strategies that can simultaneously affect both diseases and reduce their overlapping burden. In the absence of randomized clinical trials, researchers have taken advantage of the availability and richness of administrative databases and electronic medical records to investigate the effects of drugs on cancer risk among diabetic individuals. The majority of these studies suggest that metformin could potentially reduce cancer risk. However, the validity of this purported reduction in cancer risk is limited by several methodological flaws either in the study design or in the analysis. Whether metformin use decreases cancer risk relies heavily on the availability of valid data sources with complete information on confounders, accurate assessment of drug use, appropriate study design, and robust analytical techniques. The majority of the observational studies assessing the association between metformin and cancer risk suffer from methodological shortcomings and efforts to address these issues have been incomplete. Future investigations on the association between metformin and cancer risk should clearly address the methodological issues due to confounding by indication, prevalent user bias, and time-related biases. Although the proposed strategies do not guarantee a bias-free estimate for the association between metformin and cancer, they will reduce synthesis of and reporting of erroneous results.

  10. Fungal Aflatoxins Reduce Respiratory Mucosal Ciliary Function

    Science.gov (United States)

    Lee, Robert J.; Workman, Alan D.; Carey, Ryan M.; Chen, Bei; Rosen, Phillip L.; Doghramji, Laurel; Adappa, Nithin D.; Palmer, James N.; Kennedy, David W.; Cohen, Noam A.

    2016-01-01

    Aflatoxins are mycotoxins secreted by Aspergillus flavus, which can colonize the respiratory tract and cause fungal rhinosinusitis or bronchopulmonary aspergillosis. A. flavus is the second leading cause of invasive aspergillosis worldwide. Because many respiratory pathogens secrete toxins to impair mucociliary immunity, we examined the effects of acute exposure to aflatoxins on airway cell physiology. Using air-liquid interface cultures of primary human sinonasal and bronchial cells, we imaged ciliary beat frequency (CBF), intracellular calcium, and nitric oxide (NO). Exposure to aflatoxins (0.1 to 10 μM; 5 to 10 minutes) reduced baseline (~6–12%) and agonist-stimulated CBF. Conditioned media (CM) from A. fumigatus, A. niger, and A. flavus cultures also reduced CBF by ~10% after 60 min exposure, but effects were blocked by an anti-aflatoxin antibody only with A. flavus CM. CBF reduction required protein kinase C but was not associated with changes in calcium or NO. However, AFB2 reduced NO production by ~50% during stimulation of the ciliary-localized T2R38 receptor. Using a fluorescent reporter construct expressed in A549 cells, we directly observed activation of PKC activity by AFB2. Aflatoxins secreted by respiratory A. flavus may impair motile and chemosensory functions of airway cilia, contributing to pathogenesis of fungal airway diseases. PMID:27623953

  11. Microhabitats reduce animal's exposure to climate extremes.

    Science.gov (United States)

    Scheffers, Brett R; Edwards, David P; Diesmos, Arvin; Williams, Stephen E; Evans, Theodore A

    2014-02-01

    Extreme weather events, such as unusually hot or dry conditions, can cause death by exceeding physiological limits, and so cause loss of population. Survival will depend on whether or not susceptible organisms can find refuges that buffer extreme conditions. Microhabitats offer different microclimates to those found within the wider ecosystem, but do these microhabitats effectively buffer extreme climate events relative to the physiological requirements of the animals that frequent them? We collected temperature data from four common microhabitats (soil, tree holes, epiphytes, and vegetation) located from the ground to canopy in primary rainforests in the Philippines. Ambient temperatures were monitored from outside of each microhabitat and from the upper forest canopy, which represent our macrohabitat controls. We measured the critical thermal maxima (CTmax ) of frog and lizard species, which are thermally sensitive and inhabit our microhabitats. Microhabitats reduced mean temperature by 1-2 °C and reduced the duration of extreme temperature exposure by 14-31 times. Microhabitat temperatures were below the CTmax of inhabitant frogs and lizards, whereas macrohabitats consistently contained lethal temperatures. Microhabitat temperatures increased by 0.11-0.66 °C for every 1 °C increase in macrohabitat temperature, and this nonuniformity in temperature change influenced our forecasts of vulnerability for animal communities under climate change. Assuming uniform increases of 6 °C, microhabitats decreased the vulnerability of communities by up to 32-fold, whereas under nonuniform increases of 0.66 to 3.96 °C, microhabitats decreased the vulnerability of communities by up to 108-fold. Microhabitats have extraordinary potential to buffer climate and likely reduce mortality during extreme climate events. These results suggest that predicted changes in distribution due to mortality and habitat shifts that are derived from macroclimatic samples and that assume

  12. Uranium Immobilization by Sulfate-reducing Biofilms

    International Nuclear Information System (INIS)

    Hexavalent uranium [U(VI)] was immobilized using biofilms of the sulfate-reducing bacterium (SRB) Desulfovibrio desulfuricans G20. The biofilms were grown in flat-plate continuous-flow reactors using lactate as the electron donor and sulfate as the electron acceptor. U(VI) was continuously fed into the reactor for 32 weeks at a concentration of 126 ?M. During this time, the soluble U(VI) was removed (between 88 and 96% of feed) from solution and immobilized in the biofilms. The dynamics of U immobilization in the sulfate-reducing biofilms were quantified by estimating: (1) microbial activity in the SRB biofilm, defined as the hydrogen sulfide (H2S) production rate and estimated from the H2S concentration profiles measured using microelectrodes across the biofilms; (2) concentration of dissolved U in the solution; and (3) the mass of U precipitated in the biofilm. Results suggest that U was immobilized in the biofilms as a result of two processes: (1) enzymatically and (2) chemically, by reacting with microbially generated H2S. Visual inspection showed that the dissolved sulfide species reacted with U(VI) to produce a black precipitate. Synchrotron-based U L3-edge X-ray absorption near edge structure (XANES) spectroscopy analysis of U precipitated abiotically by sodium sulfide indicated that U(VI) had been reduced to U(IV). Selected-area electron diffraction pattern and crystallographic analysis of transmission electron microscope lattice-fringe images confirmed the structure of precipitated U as being that of uraninite

  13. Reduce proton energy spread by target ablation

    CERN Document Server

    Zhao, Shuan; Chen, Jiaer; Yan, Xueqing

    2015-01-01

    It's shown that, with strong target ablation monoenergetic protons along the laser direction is available during the laser aluminum foil interaction, which is different from the classic TNSA theory. When the laser pre-pulse is too strong that the whole target is vaporized, the energetic electrons generated in the gas preplasma will play an important role for the ion acceleration because the sheath field will not be available. These electrons beam, which is highly directional, will setup triangle envelope acceleration field along the laser direction at the target rear, reducing the ion energy spread.

  14. Lubrication System with Tolerance for Reduced Gravity

    Science.gov (United States)

    Portlock, Lawrence E. (Inventor); McCune, Michael E. (Inventor); Dobek, Louis J. (Inventor)

    2013-01-01

    A lubrication system includes an auxiliary lubricant tank 48, a supply conduit 58 extending from a source of lubricant 26 to the auxiliary lubricant tank. A reduced-G bypass line 108 branches from the conduit and enters the auxiliary tank at a first elevation E.sub.1. The system also includes an auxiliary tank discharge conduit 116, a portion of which resides within the tank. The resident portion has an opening 122 at least partially at a second elevation E.sub.2 higher than the first elevation.

  15. Spectroscopic Speciation of Plutonium Reduced by Electrolysis

    International Nuclear Information System (INIS)

    The oxidation state of plutonium should be carefully controlled to understand the chemical behaviors of plutonium. Pu(III) is not stable in aqueous solutions and easily oxidized in the atmosphere. In deep geological environments excluded oxygen, reducing condition is expected and will lead to rather stable Pu(III), which is very soluble compared to Pu(IV). Pu(III) ions are expected to form hydrolysis complexes in neutral and basic solutions similar to Am(III), Cm(III) and Eu(III). The reported formation constants of Pu(OH)n3-n (n=1-4) had been critically discussed, and only the first hydrolysis constant (log*β011 = -6.9 ± 0.3) was selected in a review. The main reason for the large discrepancy of the formation constants for Pu(OH)n3-n (n=2-4) is the high tendency of oxidation of Pu(III). In the present study, the reduction condition of Pu(III) was controlled by electrolysis. The electrolysis reactor was specially designed to investigate hydrolysis, colloid formation, and solubility of Pu(III) at different pHs. Pu(III) was reduced from higher oxidation states at acidic conditions, and the H+ ion concentration in solutions was simultaneously decreased without the addition of alkaline solution by electrolysis. The soluble species was investigated using spectrophotometry adopting a capillary cell (LWCC, Liquid Waveguide Capillary Cell, WPI) and the formation of plutonium colloid and solubility was determined using LIBD (Laser Induced Breakdown Detection). In this study, an electrolysis system for the reduction of plutonium and H+ ions in a solution with small volume (> 2 mL) was installed in a glove box to investigate the hydrolysis, colloid formation and solubility of Pu(III) under a reducing condition. Pu(III) was reduced from the mixed plutonium oxidation states without the generation of Pu(IV) colloidal particles or precipitates under weak acidic conditions. A coulometric titration method was applied to adjust the pH without the addition of NaOH. The change of

  16. Environment, Renewable Energy and Reduced Carbon Emissions

    Science.gov (United States)

    Sen, S.; Khazanov, G.; Kishimoto, Y.

    2011-01-01

    Increased energy security and reduced carbon emissions pose significant challenges for science and technology. However, they also create substantial opportunities for innovative research and development. In this review paper, we highlight some of the key opportunities and mention public policies that are needed to enable the efforts and to maximize the probability of their success. Climate is among the uttermost nonlinear behaviors found around us. As recent studies showed the possible effect of cosmic rays on the Earth's climate, we investigate how complex interactions between the planet and its environment can be responsible for climate anomalies.

  17. Reduced Quantum General Relativity in Higher Dimensions

    CERN Document Server

    Glinka, Lukasz Andrzej

    2016-01-01

    The higher dimensional Quantum General Relativity of a Riemannian manifold being an embedded space in a space-time being a Lorentzian manifold is investigated. The model of quantum geometrodynamics, based on the Wheeler-DeWitt equation reduced to a first order functional quantum evolution supplemented through an additional eigenequation for the scalar curvature, is formulated. Furthermore, making use of the objective quantum gravity and global one-dimensional conjecture, the general wave function beyond the Feynman path integral technique is derived. The resulting quantum gravity model creates the opportunity of potentially new theoretical and phenomenological applications for astrophysics, cosmology, and physics.

  18. Novel Reduced-Feedback Wireless Communication Systems

    KAUST Repository

    Shaqfeh, Mohammad Obaidah

    2011-11-20

    Modern communication systems apply channel-aware adaptive transmission techniques and dynamic resource allocation in order to exploit the peak conditions of the fading wireless links and to enable significant performance gains. However, conveying the channel state information among the users’ mobile terminals into the access points of the network consumes a significant portion of the scarce air-link resources and depletes the battery resources of the mobile terminals rapidly. Despite its evident drawbacks, the channel information feedback cannot be eliminated in modern wireless networks because blind communication technologies cannot support the ever-increasing transmission rates and high quality of experience demands of current ubiquitous services. Developing new transmission technologies with reduced-feedback requirements is sought. Network operators will benefit from releasing the bandwidth resources reserved for the feedback communications and the clients will enjoy the extended battery life of their mobile devices. The main technical challenge is to preserve the prospected transmission rates over the network despite decreasing the channel information feedback significantly. This is a noteworthy research theme especially that there is no mature theory for feedback communication in the existing literature despite the growing number of publications about the topic in the last few years. More research efforts are needed to characterize the trade-off between the achievable rate and the required channel information and to design new reduced-feedback schemes that can be flexibly controlled based on the operator preferences. Such schemes can be then introduced into the standardization bodies for consideration in next generation broadband systems. We have recently contributed to this field and published several journal and conference papers. We are the pioneers to propose a novel reduced-feedback opportunistic scheduling scheme that combines many desired features

  19. Reducing gain shifts in photomultiplier tubes

    Science.gov (United States)

    Cohn, Charles E.

    1976-01-01

    A means is provided for reducing gain shifts in multiplier tubes due to varying event count rates. It includes means for limiting the number of cascaded, active dynodes of the multiplier tube to a predetermined number with the last of predetermined number of dynodes being the output terminal of the tube. This output is applied to an amplifier to make up for the gain sacrificed by not totally utilizing all available active stages of the tube. Further reduction is obtained by illuminating the predetermined number of dynodes with a light source of such intensity that noise appearing at the output dynode associated with the illumination is negligible.

  20. Hydrodynamic approaches to reducing membrane fouling

    Energy Technology Data Exchange (ETDEWEB)

    Davis, R.H. [Univ. of Colorado, Boulder, CO (United States)

    1995-12-01

    Membranes are gaining increasing use in a wide variety of liquid and gas separations. A pervasive problem is membrane fouling due to material depositing on the membrane surface and within the membrane pore structure. Professor Georges Belfort has made significant contributions to reducing membrane fouling by hydrodynamic approaches for ultrafiltration and microfiltration. I will review some of his work, as well as related work by myself and others, in this area. Topics which will be discussed include particle migration during crossflow filtration, curved channels which promote centrifugal instabilities, and rapid backpulsing.