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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. 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.

  3. Chloroquine Phosphate Oral

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    Chloroquine phosphate is in a class of drugs called antimalarials and amebicides. It is used to prevent and treat ... Chloroquine phosphate comes as a tablet to take by mouth. For prevention of malaria in adults, one dose is ...

  4. PSYCHIATRIC COMPLICATIONS OF CHLOROQUINE

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    Bhatia, M.S.; S.C. Malik

    1994-01-01

    Sixty patients with chloroquine induced psychiatric complications are reported in the present series. Psychosis was the most common complication followed by anxiety state and seizures. The maximum number of patients were between the ages of 6 and 10 years and females (70.0%) outnumbered the males (30.0%). Headache and sleeplessness were found to be more common amongpatients developing psychiatric complications of chloroquine. The symptoms disappeared within 2 to 21 days after the discontinuat...

  5. 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...

  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.

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    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. New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial).

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    Peymani, Payam; Yeganeh, Behzad; Sabour, Siamak; Geramizadeh, Bita; Fattahi, Mohammad Reza; Keyvani, Hossein; Azarpira, Negar; Coombs, Kevin M; Ghavami, Saied; Lankarani, Kamran B

    2016-06-01

    Hepatitis C virus (HCV) infection induces autophagy, but the virus assimilates the autophagic response into its own life cycle. Chloroquine (CQ) is an autophagy inhibitor that is clinically used to treat malaria. The aims of this pilot clinical trial were to evaluate the therapeutic potential and short-term safety of CQ in patients with chronic HCV genotype 1, who were unresponsive to a combination of pegylated interferon alpha and ribavirin. Ten non-responders to previous antiviral treatment(s) were randomized to receive either CQ (150 mg daily for 8 weeks) or placebo, and were followed for 4 weeks after CQ therapy. HCV RNA load and plasma alanine transaminase (ALT) levels were measured at baseline, week 4 (initial response), week 8 (end-of-treatment response), and at the end of 12 weeks. A significant decrease in HCV RNA after the treatments (week 8) was observed in all patients in the CQ group (P = 0.04). However, HCV RNA levels increased within 4 weeks after discontinuation of CQ treatment although they were still lower than baseline. In addition, the ALT normalized during treatment in the CQ group. However, this response was also lost after treatment cessation. This study provides preliminary evidence that CQ is possibly a safe treatment option for HCV non-responders. PMID:26998724

  10. Secretion of phosphomannosyl-deficient arylsulphatase A and cathepsin D from isolated human macrophages.

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    Muschol, Nicole; Matzner, Ulrich; Tiede, Stephan; Gieselmann, Volkmar; Ullrich, Kurt; Braulke, Thomas

    2002-12-15

    The transfer of macrophage-secreted arylsulphatase A (ASA) to enzyme-deficient brain cells is part of the therapeutic concept of bone marrow transplantation in lysosomal storage diseases. Here we have investigated this transfer in vitro. The uptake of (125)I-labelled recombinant human ASA purified from ASA-overexpressing mouse embryonic fibroblasts deficient for mannose 6-phosphate (M6P) receptors in a mouse ASA-deficient astroglial cell line was completely inhibited by M6P. In contrast, when ASA-deficient astroglial cells were incubated with secretions of [(35)S]methionine-labelled human macrophages or mouse microglia, containing various lysosomal enzymes, neither ASA nor cathepsin D (CTSD) were detected in acceptor cells. Co-culturing of metabolically labelled macrophages with ASA-deficient glial cells did not result in an M6P-dependent transfer of ASA or CTSD between these two cell types. In secretions of [(33)P]phosphate-labelled macrophages no or weakly phosphorylated ASA and CTSD precursor polypeptides were found, whereas both intracellular and secreted ASA from ASA-overexpressing baby hamster kidney cells displayed (33)P-labelled M6P residues. Finally, the uptake of CTSD from secretions of [(35)S]methionine-labelled macrophages in rat hepatocytes was M6P-independent. These data indicated that lysosomal enzymes secreted by human macrophages or a mouse microglial cell line cannot be endocytosed by brain cells due to the failure to equip newly synthesized lysosomal enzymes with the M6P recognition marker efficiently. The data suggest that other mechanisms than the proposed M6P-dependent secretion/recapture of lysosomal enzymes might be responsible for therapeutic effects of bone marrow transplantation in the brain. PMID:12296771

  11. 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...

  12. 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

  13. Basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH

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    Krogstad, D.J.; Schlesinger, P.H.

    1987-03-01

    Biologically active concentrations of chloroquine increase the pH of the parasite's acid vesicles within 3-5 min. This increase in pH results from two mechanisms, one of which is markedly reduced in chloroquine-resistant parasites. Because chloroquine is a weak base, it increases vesicle pH by that mechanism in chloroquine-susceptible and resistant parasites and mammalian cells (based on its two pKs and on the delta pH between the acid vesicle and the extracellular environment). In chloroquine-susceptible parasites, but not resistant parasites or mammalian cells, chloroquine increases the pH of acid vesicles 700- to 800-fold more than can be accounted for by its properties as a weak base. The increase in acid vesicle pH caused by these non-weak base effects of nanomolar chloroquine in susceptible parasites suggests that chloroquine acts by interfering with acid vesicle functions in the parasite such as the endocytosis and proteolysis of hemoglobin, and the intracellular targeting of lysosomal enzymes. The non-weak base effects of nanomolar chloroquine on parasite vesicle pH are also responsible for its safety because these chloroquine concentrations do not affect mammalian cells.

  14. Plasmodium vivax trophozoites insensitive to chloroquine

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    Jaidee Anchalee

    2008-05-01

    Full Text Available Abstract Background Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax. Methods The in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27 was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment. Results Plasmodium vivax isolates added to the assay at ring stage had significantly lower median IC50s to chloroquine than the same isolates added at trophozoite stage (median IC50 12 nM vs 415 nM p P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM. Conclusion Data from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum.

  15. Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan

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    Wangchuk, Sonam; Drukpa, Tobgyel; Penjor, Kinley; Peldon, Tashi; Dorjey, Yeshey; Dorji, Kunzang; Chhetri, Vishal; Trimarsanto, Hidayat; To, Sheren; Murphy, Amanda; von Seidlein, Lorenz; Price, Ric N.; Thriemer, Kamala; Auburn, Sarah

    2016-01-01

    Background Bhutan has made substantial progress in reducing malaria incidence. The national guidelines recommend chloroquine (CQ) and primaquine (PQ) for radical cure of uncomplicated Plasmodium vivax, but the local efficacy has not been assessed. The impact of cases imported from India on the genetic make-up of the local vivax populations is currently unknown. Methods Patients over 4 years of age with uncomplicated P. vivax mono-infection were enrolled into a clinical efficacy study and mole...

  16. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase.

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    Fang, H; Liu, A; Dahmen, U; Dirsch, O

    2013-01-01

    The anti-malaria drug chloroquine is well known as autophagy inhibitor. Chloroquine has also been used as anti-inflammatory drugs to treat inflammatory diseases. We hypothesized that chloroquine could have a dual effect in liver ischemia/reperfusion (I/R) injury: chloroquine on the one hand could protect the liver against I/R injury via inhibition of inflammatory response, but on the other hand could aggravate liver I/R injury through inhibition of autophagy. Rats (n=6 per group) were pre-treated with chloroquine (60 mg/kg, i.p.) 1 h before warm ischemia, and they were continuously subjected to a daily chloroquine injection for up to 2 days. Rats were killed 0.5, 6, 24 and 48 h after reperfusion. At the early phase (i.e., 0-6 h after reperfusion), chloroquine treatment ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines and fewer histopathologic changes. In contrast, chloroquine worsened liver injury at the late phase of reperfusion (i.e., 24-48 h after reperfusion). The mechanism of protective action of chloroquine appeared to involve its ability to modulate mitogen-activated protein kinase activation, reduce high-mobility group box 1 release and inflammatory cytokines production, whereas chloroquine worsened liver injury via inhibition of autophagy and induction of hepatic apoptosis at the late phase. In conclusion, chloroquine prevents ischemic liver damage at the early phase, but aggravates liver damage at the late phase in liver I/R injury. This dual role of chloroquine should be considered when using chloroquine as an inhibitor of inflammation or autophagy in I/R injury. PMID:23807223

  17. 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

  18. 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.

  19. 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.

  20. 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. PMID:26420308

  1. 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.

  2. Antimuscarinic effects of chloroquine in rat pancreatic acini

    International Nuclear Information System (INIS)

    Chloroquine inhibited carbachol-induced amylase release in a dose-dependent fashion in rat pancreatic acini; cholecystokinin- and bombesin-induced secretory responses were almost unchanged by the antimalarial drug. The inhibition of carbachol-induced amylase release by chloroquine was competitive in nature with a K/sub i/ of 11.7 μM. Chloroquine also inhibited [3H]N-methylscopolamine binding to acinar muscarinic receptors. The IC50 for chloroquine inhibition of [3H]N-methylscopolamine binding was lower than that for carbachol or the other antimalarial drugs, quinine and quinidine. These results demonstrate that chloroquine is a muscarinic receptor antagonist in the exocrine pancreas

  3. 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.

  4. 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. PMID:25898991

  5. 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.

  6. 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...

  7. 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...

  8. 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

  9. Return of Chloroquine-Susceptible Falciparum Malaria in Malawi Was a Reexpansion of Diverse Susceptible Parasites

    OpenAIRE

    Laufer, Miriam K; Takala-Harrison, Shannon; Dzinjalamala, Fraction K.; Stine, O. Colin; Taylor, Terrie E.; Plowe, Christopher V.

    2010-01-01

    The spread of drug-resistant Plasmodium falciparum malaria has been a major impediment to malaria control and threatens prospects for elimination. We recently demonstrated the return of chloroquine-susceptible malaria in Malawi after chloroquine use was abandoned. In this study, we trace the origins of chloroquine-resistant and chloroquine-susceptible parasites in Malawi by sequencing the P. falciparum chloroquine resistance transporter gene (pfcrt) and by genotyping microsatellites flanking ...

  10. 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

    Directory of Open Access Journals (Sweden)

    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

  11. 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

  12. Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

    Directory of Open Access Journals (Sweden)

    Greenwood Brian

    2008-12-01

    Full Text Available Abstract In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp with sulphadoxine-pyrimethamine (SP reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp.

  13. Chloroquine Transport in Plasmodium falciparum I: Influx and Efflux Kinetics for Live Trophozoite Parasites using a Novel Fluorescent Chloroquine Probe

    OpenAIRE

    Cabrera, Mynthia; Natarajan, Jayakumar; Paguio, Michelle F.; Wolf, Christian; Urbach, Jeffrey S.; Roepe, Paul D.

    2009-01-01

    Several models for how amino acid substitutions in the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Distinguishing between these models requires detailed analysis of high resolution CQ transport data that is unfortunately impossible to obtain with traditional radio–tracer methods. Thus, we have designed and synthesized fluorescent CQ analogues for drug transport studies. One probe places...

  14. Chloroquine mediated modulation of Anopheles gambiae gene expression.

    Directory of Open Access Journals (Sweden)

    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.

  15. Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

    Directory of Open Access Journals (Sweden)

    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.

  16. 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...

  17. Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

    OpenAIRE

    Pou, Sovitj; Winter, Rolf W.; Nilsen, Aaron; Kelly, Jane Xu; Li, Yuexin; Doggett, J. Stone; Riscoe, Erin W.; Wegmann, Keith W.; Hinrichs, David J.; Riscoe, Michael K.

    2012-01-01

    Sontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains of Plasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents...

  18. In vivo confocal microscopy in chloroquine-induced keratopathy

    Directory of Open Access Journals (Sweden)

    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.

  19. Stability of chloroquine phosphate tablets inoculated with bacterial species

    International Nuclear Information System (INIS)

    Five popular brands of chloroquine tablets available to the average Nigerian consumers were examined for the effects of Staphylococcus aureus and Bacillus cereus, on the dissolution, disintegration and hardness after six weeks of incubation. The maximum percent dissolution was 98.34% with bacillus subtilis while the minimum was 19.12% with staphylococcus aureus. The disintegration results showed a maximum of 69 min. 19 sec with Staphylococcus aureus while the least was 56 sec with Bacillus subtilis. The maximum hardness obtained was 12.75 kg and the least was 1.25 kg also with Staphylococcus aureus. The dissolution, disintegration and hardness also varied with the control. The metabolic activities of the bacterial species were believed to have caused the variations in the physical properties of the chloroquine phosphate tablets. The results from this investigation strongly advises adequate storage of chloroquine phosphate tablets, especially when it is the drug of choice for the of sub-Saharan Africa. (author)

  20. 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

    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...

  1. 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 with the...... 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...

  2. 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 of...... an alternative dosing of CQ may overcome resistance in Africa....

  3. 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.

  4. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Chloroquine resistance in Pakistan and the upsurge of falciparum malaria in Pakistani and Afghan refugee populations.

    Science.gov (United States)

    Shah, I; Rowland, M; Mehmood, P; Mujahid, C; Razique, F; Hewitt, S; Durrani, N

    1997-09-01

    Surveys conducted in Pakistan during the last decade show that falciparum malaria has become resistant to chloroquine in Pakistani and Afghan refugee populations throughout the country. Although RI resistance is common everywhere (with a frequency of 30%-84%), RII is rarer (2%-36%), and RIII resistance has yet to be detected. The national policy is to prescribe chloroquine as first-line treatment of malaria. A repeated in-vivo survey in a sentinel village indicated that prescription of chloroquine can lead to a 15% increase in the frequency of resistance in a single year, and similar trends were observed in other districts. Coinciding with the spread of resistance is a 6-fold increase in the number of falciparum cases recorded nationally between 1982 and 1992 and a parallel, 5-fold increase in the number of cases recorded in the Afghan refugee population. Resistance contributes to this trend in various ways. Firstly, patients with resistant malaria make repeated visits to health centres. In the sentinel village, for example, where resistance was measured at 71%, recrudescent infections inflated by 66% the genuine incidence of new infections recorded at the health centre. Secondly, owing to ineffective treatment, resistant infections are often still patent during the post-transmission season. This may enlarge the 'overwintering' parasite reservoir, leading to a surge of new cases when transmission resumes. Other factors potentially contributing to the upsurge in falciparum include the decrease availability of insecticide for indoor spraying. Despite the problems posed by resistance for case management, the evidence from the vector-control programme among the refugees is that malaria control through well-targeted campaigns of insecticide spraying is still able to reduce the incidence of falciparum malaria to a level that existed before the advent of resistance. PMID:9425361

  7. Chloroquine-induced scratching is mediated by NO/cGMP pathway in mice.

    Science.gov (United States)

    Foroutan, Arash; Haddadi, Nazgol Sadat; Ostadhadi, Sattar; Sistany, Narges; Dehpour, Ahmad Reza

    2015-07-01

    Chloroquine (CQ), a 4-aminoquinoline drug, has long been used in the treatment and prevention of malaria. However its side effect generalized pruritus contributes to treatment failures, and consequently results in the development of chloroquine resistant strains of Plasmodium falciparum. It was proposed that the administration of CQ correlated with increase in nitric oxide (NO) production. Nitric oxide is involved in some pruritic disorders such as atopic dermatitis, psoriasis and scratching behavior evoked by pruritogens like substance P. Therefore, the aim of this study was to investigate the involvement of NO/cGMP pathway in CQ-induced scratching in mice. Scratching behaviors were recorded by a camera after intradermal (ID) injection of CQ in the shaved rostral back of the mice. The results obtained show that CQ elicited scratching in a dose-dependent manner with a peak effective dose of 400μg/site. Injection of non-specific NOS inhibitor, N-nitro-l-arginine methyl ester or neuronal NOS selective inhibitor and 7-nitroindazole, reduced CQ-induced scratching significantly. On the other hand, administration of aminoguanidine as inducible NOS inhibitor has no inhibitory effect on this behavior. Also, injection of l-arginine as a precursor of NO significantly increased this response. Conversely, accumulation of cGMP by sildenafil as a selective phosphodiesterase type 5 inhibitor, potentiated the scratching behavior by CQ. This study therefore shows that CQ-induced scratching behavior is mediated by the NO/cGMP pathway. PMID:25957523

  8. Battling the malaria iceberg with chloroquine in India

    OpenAIRE

    Sharma Vinod P

    2007-01-01

    Abstract The National Vector Borne Disease Control Programme (NVBDCP) of the Ministry of Health, Government of India is reporting about 2 million parasite positive cases each year, although case incidence is 30-fold or more under-estimated. Forty five to fifty percent of Plasmodium infections are caused by Plasmodium falciparum, the killer parasite. Anti-malaria drug policy (2007) of the NVBDC recommends chloroquine (CQ) as the first line of drug for the treatment of all malarias. In a Primar...

  9. 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...

  10. Influence of route of administration on the pharmacokinetics of chloroquine and desethylchloroquine

    OpenAIRE

    Salako, L A; Aderounmu, A F; Walker, O

    1987-01-01

    The pharmacokinetics of chloroquine following a single oral dose of 600 mg or an intramuscular injection of 200 mg of the drug was studied in seven healthy adult Africans. Each subject received chloroquine by both routes, with an interval of at least 4 months between them. Intramuscular injection led to rapid absorption of chloroquine, which attained a maximum concentration in plasma after 15 minutes and occasionally reached toxic levels; plasma levels fell below therapeutically useful concen...

  11. Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans.

    OpenAIRE

    Aderounmu, A F; Salako, L A; Lindström, B; Walker, O; Ekman, L

    1986-01-01

    The pharmacokinetics of chloroquine were studied after intramuscular and intravenous administration of the drug to healthy African adults. Chloroquine was analysed in plasma using an h.p.l.c. method and pharmacokinetic parameters were derived from the concentration-time data using a non-linear computer programme. A two-compartment open model was assumed. Chloroquine was rapidly absorbed from an intramuscular site, producing a plasma concentration-time profile similar to that obtained after a ...

  12. 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

    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 with...... of malaria in children in Ghana, in the presence of chloroquine resistance.......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...

  13. 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 ...

  14. 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.

  15. 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.

  16. 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

  17. 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...

  18. Fluoxetine hydrochloride enhances in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Gerena, L.; Bass, G T; Kyle, D. E.; Oduola, A M; Milhous, W K; Martin, R K

    1992-01-01

    The emergence of chloroquine resistance in Plasmodium falciparum has necessitated the development of alternate strategies for chemotherapy and chemoprophylaxis. One approach has been the identification of drugs that do not possess any intrinsic antimalarial activity when used alone but that potentiate the effect of currently available antimalarial drugs, such as chloroquine. We identified fluoxetine hydrochloride (Prozac), a commonly prescribed antidepressant, as another resistance modulator ...

  19. 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...

  20. 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.

  1. 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

  2. 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.

  3. Contrasting ex vivo efficacies of "reversed chloroquine" compounds in chloroquine-resistant Plasmodium falciparum and P. vivax isolates.

    Science.gov (United States)

    Wirjanata, Grennady; Sebayang, Boni F; Chalfein, Ferryanto; Prayoga; Handayuni, Irene; Noviyanti, Rintis; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Burgess, Steven J; Peyton, David H; Price, Ric N; Marfurt, Jutta

    2015-09-01

    Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo. Between March to October 2011 and January to September 2013, two "reversed chloroquine" (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum (n = 41) and Plasmodium vivax (n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum, the median 50% inhibitory concentrations (IC50s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P resistant clinical isolates of P. falciparum and P. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species. PMID:26149984

  4. Color vision loss in patients treated with chloroquine

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    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

  5. 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

    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......, 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 on the...... prevalence of wild types at codon 76 of the Pfcrt gene in indigenous P. falciparum populations. The current prevalence of this Pfcrt-76 CQ resistance marker from six regions of Tanzania mainland is hereby reported....

  6. 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...... amodiaquine (AQ) in 2003. Since 2006, the artemisinin combination therapies (ACTs) artemether-lumefantrine (AL) and artesunate plus amodiaquine (AS/AQ) were adopted for uncomplicated malaria treatment. After several years of CQ withdrawal, the current study wished to determine the level of CQ resistance at...... 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...

  7. Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment

    Directory of Open Access Journals (Sweden)

    TO Ogungbamigbe

    2008-02-01

    Full Text Available Chloroquine (CQ resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1% of the patients were cured and 44 (37.9% failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP and 20 received chlorpheniramine + chloroquine (CH+CQ combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05. There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92% while those of CH+CQ was 85%. There was a significant difference in parasite clearance time (p = 0.01 between the two groups. The 38% treatment failure for CQ reported in this study is higher than the 10% recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.

  8. 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

  9. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

    Science.gov (United States)

    TUOMELA, JOHANNA; SANDHOLM, JOUKO; KAUPPILA, JOONAS H.; LEHENKARI, PETRI; HARRIS, KEVIN W.; SELANDER, KATRI S.

    2013-01-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  10. 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...

  11. 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.

  12. Prevalence of Plasmodium falciparum chloroquine resistant gene markers, pfcrt-76 and pfmdr1-86, eight years after cessation of chloroquine use in Mwea, Kenya

    OpenAIRE

    Sabah Ahmed Omar,1 Francis W. Makokha,2,3 Fat’hia Abdo Mohammed,1 Francis T. Kimani,1 Gabriel Magoma3

    2007-01-01

    Background and Methodology: The prevalence of T76 and Y86 Plasmodium falciparum molecular markers for chloroquine (CQ) resistance in the Pfcrt and Pfmdr1 genes were investigated by PCR-RFLP and dot blot analysis in samples (50 for Pfcrt and 51 for Pfmdr1) collected in May 2005, eight years after chloroquine (CQ) cessation.Results: Our findings show that 94% of field isolates from this site still harbor T76 mutation in Pfcrt while 6% have the wild type allele K76 [T test, P=0.04058 (1997 versu...

  13. 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

    Chloroquine resistant malaria was first reported in Guinea-Bissau in 1990 but chloroquine remains the most commonly used antimalarial in the country. Since 1990, we have conducted nearly annual standardized WHO in vitro micro-tests to assess chloroquine resistance. We have identified pfcrt 76T 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...

  14. 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

  15. 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

  16. 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

  17. Battling the malaria iceberg with chloroquine in India

    Directory of Open Access Journals (Sweden)

    Sharma Vinod P

    2007-08-01

    Full Text Available Abstract The National Vector Borne Disease Control Programme (NVBDCP of the Ministry of Health, Government of India is reporting about 2 million parasite positive cases each year, although case incidence is 30-fold or more under-estimated. Forty five to fifty percent of Plasmodium infections are caused by Plasmodium falciparum, the killer parasite. Anti-malaria drug policy (2007 of the NVBDC recommends chloroquine (CQ as the first line of drug for the treatment of all malarias. In a Primary Health Centre (PHC reporting 10% or more cases of CQ resistance in P. falciparum, ACT blister pack is recommended and, so far, the policy has been adopted in 261 PHCs of 71 districts. The NVBDCP still depends on CQ to combat malaria and, as a result, P. falciparum has taken deep roots in malaria-endemic regions, causing unacceptable levels of morbidity and mortality. This policy was a subject of criticism in recent Nature and Lancet articles questioning the World Bank's decision to supply CQ to the NVBDCP. Continuation of an outdated drug in the treatment of P. falciparum is counterproductive in fighting drug resistant malaria and in the containment of P. falciparum. Switchover to Artemisinin-based Combination Therapy (ACT in the treatment of all P. falciparum cases, ban on artemisinin monotherapy and effective vector control (treated nets/efficient insecticide spraying would be a rational approach to malaria control in India.

  18. Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability.

    Science.gov (United States)

    Korthagen, Nicoline M; Bastiaans, Jeroen; van Meurs, Jan C; van Bilsen, Kiki; van Hagen, P Martin; Dik, Willem A

    2015-07-01

    Antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used as antiinflammatory drugs, but side effects include retinopathy and vision loss. The objective of this study was to examine the effect of CQ and HCQ on the barrier integrity of retinal pigment epithelial (RPE) cell monolayers in vitro. Permeability of ARPE-19 cell monolayers was determined using Fluorescein isothiocyanate (FITC)-labeled dextran. The influence of CQ and HCQ on cell death and the expression tight junction molecules was examined. CQ and HCQ significantly increased ARPE-19 monolayer permeability after 3 and 18 h, respectively, and enhanced mRNA levels for claudin-1 and occludin. Cytotoxicity was only observed after 18 h exposure. Thus, CQ and HCQ rapidly enhance RPE barrier permeability in vitro, independent of cytotoxicity or loss of zonula occludens-1, claudin-1, and occludin expression. Our findings suggest that CQ/HCQ-induced permeability of the RPE layer may contribute to blood-retinal barrier breakdown in case of CQ/HCQ-induced retinopathy. PMID:25752684

  19. Development and Characterization of Hydroxyl Chloroquine Sulphate (HCQ Nanoparticles

    Directory of Open Access Journals (Sweden)

    Roopkishora

    2015-01-01

    Full Text Available The objective of present study was to formulate and characterize the nanoparticles of hydroxyl chloroquine sulphate (HCQ. Nanoparticles were prepared by the w/o/w emulsion - solvent evaporation method using polymer Eudragit® RL-100, acetone, and surfactant poloxmer-188 solutions. Amount of polymer, organic solvent and surfactant was selected as formulation variable. Characterization of the nanoparticles was performed by measuring particle size, zeta potential, surface morphology, interactions, drug entrapment efficiency, in-vitro drug release, % yield and stability. The formulated nanoparticles were found to be spherical and uniform in particle size with less than one poly dispersity index. The zeta potential of nanoparticles was found -34 (mv represent higher stability of colloidal dispersion. In another set of characterization the percentage yield and entrapment was found to be in the range of 55-68% and 63.14% respectively. The in-vitro release shows 87.93% at its maximum level in 24 hours of study. The suspension of formulation was found more stable in refrigerated environment. The release kinetics evaluation revealed the drug release was following Higuchi model, which ensures the possibility of long term release profile from the nanoparticles formulation so that its concentration maintained within therapeutic level for larger period of time so that safe and efficacious for malarial and rheumatoid patients.

  20. Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance.

    Science.gov (United States)

    Lin, Jing-Wen; Spaccapelo, Roberta; Schwarzer, Evelin; Sajid, Mohammed; Annoura, Takeshi; Deroost, Katrien; Ravelli, Raimond B G; Aime, Elena; Capuccini, Barbara; Mommaas-Kienhuis, Anna M; O'Toole, Tom; Prins, Frans; Franke-Fayard, Blandine M D; Ramesar, Jai; Chevalley-Maurel, Séverine; Kroeze, Hans; Koster, Abraham J; Tanke, Hans J; Crisanti, Andrea; Langhorne, Jean; Arese, Paolo; Van den Steen, Philippe E; Janse, Chris J; Khan, Shahid M

    2015-06-01

    Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes. PMID:25941254

  1. 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

  2. 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.

  3. 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.

  4. 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. PMID:26953199

  5. 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.

  6. 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.

  7. 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...

  8. Effect of Khat (Catha edulis) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine

    Science.gov (United States)

    Issa, Faiza H.; Al-Habori, Molhem; Chance, Michael L.

    2016-01-01

    Objectives: This study aimed to evaluate the effect of khat (Catha edulis) on chloroquine (CQ) bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. Methods: This study took place between January and April 2007 in Bajil and Sana’a, Yemen. Two CQ doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chewing for the second (phase two). Additionally, 103 patients with Plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57) and non-khat chewers (n = 46), were treated with CQ (25 mg/kg) over three days. Pharmacokinetic parameters were analysed among both controls and malaria patients. Parasite clearance was also investigated for the latter group. Results: The mean area under the concentration-time curve (AUC) was 2,108.9 versus 2,797.4 ng/hour/mL, mean peak plasma concentration (Cmax) was 415.6 versus 508.7 ng/mL and mean time to reach Cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both AUC and Cmax levels were significantly reduced by khat-chewing (P <0.050). For khat- versus non-khat-chewing malaria patients, mean plasma CQ concentrations were 266.4 ng/mL versus 427.5 ng/mL (P <0.001). Furthermore, CQ was effective in 71.7% and 75.4% of non-khat and khat-chewing malaria patients, respectively (P = 0.823). Conclusion: Khat-chewing was found to significantly reduce plasma CQ levels among healthy volunteers and malaria patients. While receiving CQ treatment, patients should be advised not to chew khat. PMID:27226909

  9. Effect of Khat (Catha edulis Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine

    Directory of Open Access Journals (Sweden)

    Faiza H. Issa

    2016-05-01

    Full Text Available Objectives: This study aimed to evaluate the effect of khat (Catha edulis on chloroquine (CQ bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. Methods: This study took place between January and April 2007 in Bajil and Sana’a, Yemen. Two CQ doses (600 mg each were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one while controls abstained from khat-chewing for the second (phase two. Additionally, 103 patients with Plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57 and non-khat chewers (n = 46, were treated with CQ (25 mg/kg over three days. Pharmacokinetic parameters were analysed among both controls and malaria patients. Parasite clearance was also investigated for the latter group. Results: The mean area under the concentration-time curve (AUC was 2,108.9 versus 2,797.4 ng/hour/mL, mean peak plasma concentration (Cmax was 415.6 versus 508.7 ng/mL and mean time to reach Cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both AUC and Cmax levels were significantly reduced by khat-chewing (P <0.050. For khat- versus non-khat-chewing malaria patients, mean plasma CQ concentrations were 266.4 ng/mL versus 427.5 ng/mL (P <0.001. Furthermore, CQ was effective in 71.7% and 75.4% of non-khat and khat-chewing malaria patients, respectively (P = 0.823. Conclusion: Khat-chewing was found to significantly reduce plasma CQ levels among healthy volunteers and malaria patients. While receiving CQ treatment, patients should be advised not to chew khat.

  10. 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.

  11. 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

  12. 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.

  13. 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...

  14. 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

    .8), between the two groups. The results suggest that syrup chloroquine and intramuscular/oral artesunate currently give comparable clinical responses in the treatment of cerebral malaria in Ghana. Possible reasons for this are discussed, and suggestions are made for future antimalarial drug policy....

  15. N'Dribala (Cochlospermum planchonii) versus chloroquine for treatment of uncomplicated Plasmodium falciparum malaria.

    Science.gov (United States)

    Benoit-Vical, F; Valentin, A; Da, B; Dakuyo, Z; Descamps, L; Mallié, M

    2003-11-01

    The aim of this work was to assess the efficacy of oral N'Dribala (tuberous roots decoction of Cochlospermum planchonii Hook) treatment versus chloroquine in non-severe malaria. The study included 85 patients with uncomplicated Plasmodium falciparum infection in Banfora, Burkina Faso. Forty-six patients that received N'Dribala beverage were compared to 21 patients treated with chloroquine. All patients were monitored with clinical examination and a parasitemia control by Giemsa-stained thick films. N'Dribala appeared safe and statistically as efficient as chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. At day 5 (D5), 57% of chloroquine-treated and 52% of N'Dribala-treated patients were cured with no detectable parasitemia (parasite density (Pd): 0) and more than 90% of whole patients were asymptomatic. N'Dribala is easily available in this country, cheap, without significant side effects and efficient with a clearly demonstrated activity on Plasmodium falciparum blood stages. This study enhances the traditional use of the Cochlospermum planchonii as alternative therapy for treatment of non-severe malaria. PMID:14522441

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

    Directory of Open Access Journals (Sweden)

    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

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria

    OpenAIRE

    1986-01-01

    Adults with malaria in Sri Lanka were treated with parenteral chloroquine diphosphate, either 2.5 mg base/kg intramuscularly at 0, 1, 12, 13, 24, and 25 hours or 5 mg base/kg subcutaneously at 0, 12, and 24 hours. Both regimens were completed with oral chloroquine phosphate, 5 mg base/kg, at 36 and 48 hours. Mean peak chloroquine concentrations in the first 12 hours, which were 0.5 (range 0.3-0.6) mg/l (1.4 (0.9-1.7) mu mol/l) [corrected] with the intramuscular regimen and 0.3 (0.2-0.4) mg/l ...

  20. Additive effects of ciprofloxacin on the in-vitro activity of chloroquine against a clinical isolate of Plasmodium falciparum.

    Science.gov (United States)

    Kazzim, O J; Adegbolagun, O M; Osho, O; Anumudu, C I

    2006-10-01

    As chloroquine and ciprofloxacin each possess substantial inhibitory activity against the schizonts of Plasmodium falciparum, it seems possible that a combination of the two drugs may be clinically useful. The effects on the erythrocytic stages of P. falciparum of combined treatment with chloroquine and ciprofloxacin were therefore evaluated in vitro, using the World Health Organization's standardized micro test. When used alone, the median inhibitory concentration (IC(50)) of chloroquine against the schizonts in the assay mixtures was found to be 7.75 microg/ml, whereas the corresponding value for ciprofloxacin was markedly lower, at 3.35 microg/ml. When they were used together, however, there was marked and statistically significant mutual enhancement of schizont inhibition by the two drugs, indicating that a chloroquine-ciprofloxacin combination may be useful clinically, in the treatment and management of P. falciparum malaria. PMID:16989683

  1. 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...

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. The effect of chloroquine treatment in addition to steroids in idiopathic pulmonary hemosiderosis

    OpenAIRE

    İmamoğlu, Sebahat; Karakoç, Fazilet; Karadağ, Bülent; Kut, Arif; Dağlı, Elif

    2001-01-01

    Idiopatic pulmonary hemosiderosis is a rare disease characterized by iron deficiency anemia recurrent pulmonary symptoms and transient interstitial infiltrates or a miliary pattern on chest radiography There is no specific treatment for this condition Corticostreoids appear to be helpful in the management of the acute hemorrhagic episodes Chloroquine is thought to be important in treatment of idiopathic pulmonary hemosiderosis because of its lack of toxicity In this report three cases of idio...

  7. 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....

  8. Chloroquine-resistant Plasmodium vivax malaria in Serbo town, Jimma zone, south-west Ethiopia

    OpenAIRE

    Birhanu Tarekegn; Bacha Ketema; Ketema Tsige; Petros Beyene

    2009-01-01

    Abstract Background Ethiopia has the highest proportion of vivax malaria, approximately 40% of all malaria infections, in contrast to African countries. Chloroquine (CQ) is the drug of choice for the treatment of Plasmodium vivax infection in the country, although CQ resistant P. vivax (CRPv) has started to challenge the efficacy of the drug. The present study was conducted to assess the current status of CRPv at Serbo, Jimma zone, south-west Ethiopia. Methods A 28-day in vivo therapeutic eff...

  9. Chloroquine resistant vivax malaria in a pregnant woman on the western border of Thailand

    OpenAIRE

    McGready Rose; Muehlenbachs Atis; Lindegardh Niklas; Phyo Aung; Leimanis Mara L; Imwong Mallika; Russell Bruce; Boel Machteld E; Rijken Marcus J; Rénia Laurent; Snounou Georges; Singhasivanon Pratap; Nosten François

    2011-01-01

    Abstract Chloroquine (CQ) resistant vivax malaria is spreading. In this case, Plasmodium vivax infections during pregnancy and in the postpartum period were not satisfactorily cleared by CQ, despite adequate drug concentrations. A growth restricted infant was delivered. Poor susceptibility to CQ was confirmed in-vitro and molecular genotyping was strongly suggestive of true recrudescence of P. vivax. This is the first clinically and laboratory confirmed case of two high-grade CQ resistant viv...

  10. Therapeutic efficacy of chloroquine for treatment of Plasmodium vivax malaria cases in Halaba district, South Ethiopia

    Directory of Open Access Journals (Sweden)

    Bacha Ketema

    2011-03-01

    Full Text Available Abstract Background Chloroquine is an anti-malarial drug being used to treat Plasmodium vivax malaria cases in Ethiopia. However, emergence of chloroquine resistant strains of the parasite has challenged the current efficacy of the drug. Therefore, the aim of this study was to assess the effectiveness of chloroquine against P. vivax strains in one of the malaria endemic areas of Ethiopia, namely Halaba district, located in South Nations and Nationalities Peoples Region (SNNPR of South Ethiopia Results Among 87 malaria patients enrolled in the study, only 80 of them completed the 28-days follow-up. Seven of them dropped from the study for different reasons. Among those study participants that completed their follow-up, 69 were classified under the category of adequate clinical and parasitological response (ACPR. However, the remaining 11 cases were considered as under treatment failure mainly due to recurrence of parasitemia on day 7 (four patients, day 14 (six patients, and day 21 (one patient. The age of all cases of treatment failures was found to be less than 20 years. The load of parasitemia of patients with treatment failure on day of admission (4709.4/μl was higher than day of recurrence (372.37/μl. Parasite reduction ratio (PRR of treatment failure cases was 12.6/μl. Conclusion This report revealed the rise in treatment failure (13% [95% CI = 0.074 - 0.217] as compared to earlier reports from Ethiopia. It signals the spreading of chloroquine resistant P. vivax (CRPv strains to malaria endemic areas of Ethiopia. It is recommended that all concerned bodies should act aggressively before further expansion of the current drug resistant malaria.

  11. 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...

  12. Prevalence of Plasmodium falciparum chloroquine resistant gene markers, pfcrt-76 and pfmdr1-86, eight years after cessation of chloroquine use in Mwea, Kenya

    Directory of Open Access Journals (Sweden)

    Sabah Ahmed Omar,1 Francis W. Makokha,2,3 Fat’hia Abdo Mohammed,1 Francis T. Kimani,1 Gabriel Magoma3

    2007-10-01

    Full Text Available Background and Methodology: The prevalence of T76 and Y86 Plasmodium falciparum molecular markers for chloroquine (CQ resistance in the Pfcrt and Pfmdr1 genes were investigated by PCR-RFLP and dot blot analysis in samples (50 for Pfcrt and 51 for Pfmdr1 collected in May 2005, eight years after chloroquine (CQ cessation.Results: Our findings show that 94% of field isolates from this site still harbor T76 mutation in Pfcrt while 6% have the wild type allele K76 [T test, P=0.04058 (1997 versus 2005]. Dot blot analysis revealed that most of the isolates had MET polymorphism at position 74, 75 and 76 wild type allele of the Pfcrt gene. When Pfmdr1-86 was analyzed by dot blot, 6% of the isolates had wild type allele N86, 73% had mutant allele Y86, and 21% had both N and Y [T test, P=0.04058 (1997 versus 2005].Conclusions: Dot blot hybridization was found to be more sensitive and specific than PCR-RFLP. The study showed a moderate reversal to sensitivity by the P. falciparum population in the study site compared to the situation before CQ cessation.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. In silico attempt for adduct agent(s) against malaria: Combination of chloroquine with alkaloids of Adhatoda vasica.

    Science.gov (United States)

    Swain, Shasank S; Sahu, Mahesh C; Padhy, Rabindra N

    2015-10-01

    With the aim of controlling drug resistant Plasmodium falciparum, a computational attempt of designing novel adduct antimalarial drugs through the molecular docking method of combining chloroquine with five alkaloids, individually is presented. These alkaloids were obtained from the medicinal plant, Adhatoda vasica. From the obtained individual docking values of important derivatives of quinine and chloroquine, as well as, individual alkaloids and adduct agents of chloroquine with Adhatoda alkaloids as ligands, it was discernible that the 'adduct agent-1 with chloroquine and adhatodine' combination had the minimum energy of interaction, as the docking score value of -11.144 kcal/mol against the target protein, triosephosphate isomerase (TIM), the key enzyme of glycolytic pathway. Drug resistance of P. falciparum is due to a mutation in the polypeptide of TIM. Moratorium of mutant TIM would disrupt the metabolism during the control of the drug resistant P. falciparum. This in silico work helped to locate the 'adduct agent-1 with chloroquine and adhatodine', which could be taken up by pharmacology for further development of this compound as a new drug against drug resistant Plasmodium. PMID:26142781

  18. Dynamic of plasmodium falciparum chloroquine resistance transporter gene Pfcrt K76T mutation five years after withdrawal of chloroquine in Burkina Faso.

    Science.gov (United States)

    Sondo, Paul; Derra, Karim; Tarnagda, Zekiba; Nakanabo, Seydou Diallo; Zampa, Odile; Kazienga, Adama; Valea, Innocent; Sorgho, Hermann; Ouedraogo, Jean-Bosco; Guiguemde, Tinga Robert; Tinto, Halidou

    2015-01-01

    We investigated the evolution of Pfcrt K76T mutation five years after the withdrawal of chloroquine in Burkina Faso. A total of 675 clinical isolates collected from October 2010 to September 2012 were successfully genotyped. Single nucleotide polymorphism in Pfcrt (codon 76) gene was analyzed. The prevalence of resistant Pfcrt 76T allele was 20.55%. There was a progressive decrease of the proportion of mutant type pfcrt T76 from 2010 to 2012 (X2=5.508 p=0.0189). Our results suggest a progressive return of the wild type Pfcrt K76 in Burkina Faso but the prevalence of the mutants Pfcrt T76 still remains high. PMID:26516402

  19. 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

  20. 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

  1. 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

    OpenAIRE

    Helena Gama; Aldo Ismael; Felicidade Sitoi; André Matola; Henrique Barros; Nuno Lunet

    2009-01-01

    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 a...

  2. 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...

  3. 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

  4. Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine

    OpenAIRE

    Navarro, Maribel; Castro, William; Higuera-Padilla, Angel R; Sierraalta, Anibal; Abad, María Jesús; Taylor, Peter; Sánchez-Delgado, Roberto A.

    2011-01-01

    Three platinum-chloroquine complexes, trans-Pt(CQDP)2(I)2 [1], trans-Pt(CQDP)2(Cl)2 [2] and trans-Pt(CQ)2(Cl)2 [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contrib...

  5. 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.

  6. 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....

  7. Effect of Khat (Catha edulis) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine

    OpenAIRE

    Faiza H. Issa; Molhem Al-Habori; Chance, Michael L.

    2016-01-01

    Objectives: This study aimed to evaluate the effect of khat (Catha edulis) on chloroquine (CQ) bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. Methods: This study took place between January and April 2007 in Bajil and Sana’a, Yemen. Two CQ doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chew...

  8. 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...

  9. Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

    Science.gov (United States)

    Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

    2015-09-01

    Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. PMID:26213237

  10. 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

  11. 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

  12. Effects of pristane alone or combined with chloroquine on macrophage activation, oxidative stress, and TH1/TH2 skewness.

    Science.gov (United States)

    Ouyang, Qiufang; Huang, Ziyang; Wang, Zhenhua; Chen, Xiaoqing; Ni, Jingqin; Lin, Ling

    2014-01-01

    We investigated the protective role of chloroquine against pristane-induced macrophage activation, oxidative stress, and Th1/Th2 skewness in C57BL/6J mice. Those mice were treated with pristane alone or combined with chloroquine. Hematological and biochemical parameters, macrophage phagocytic function, the oxidant/antioxidant index, cytokine for IFN-γ, TNF-α, IL-4, and IL-6, and the isotypes of IgG2a and IgG1 were determined. And the expression of T-bet/GATA-3 and IL-12/IL-10 mRNA in spleen were analyzed by real-time PCR. We found that pristane treatment for a period of 12 or 24 weeks triggered macrophage activation syndrome, characterized by hemophagocytosis in spleen and peripheral blood, enhanced lipid phagocytosis by peritoneal macrophages in vitro, erythropenia and leucopenia, increased anti-Smith, lactic dehydrogenase, triglyceride, and ferritin, as well as hypercytokinemia of IFN-γ, TNF-α, IL-4, and IL-6. In parallel, a significant increase in lipid peroxidation and a decrease in superoxide dismutase, glutathione, and catalase activity, as well as a skewed Th1/Th2 balance in spleen, were observed. However, chloroquine supplementation showed a remarkable amelioration of these abnormalities. Our data indicate that pristane administration induces macrophage activation, oxidative stress, and Th1/Th2 skewness, which can be attenuated by chloroquine. PMID:25136646

  13. Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules.

    Science.gov (United States)

    Ferraris, O; Moroso, M; Pernet, O; Emonet, S; Ferrier Rembert, A; Paranhos-Baccalà, G; Peyrefitte, C N

    2015-06-01

    Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 μM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing. PMID:25796972

  14. Is chloroquine still effective for the treatment of vivax malaria in children in northern punjab of pakistan?

    International Nuclear Information System (INIS)

    Introduction: Every year more than one billion persons in the world suffer from malaria. It kills about 1-3 million people in the world per year. In Pakistan estimated burden of malaria is 1.6 million cases each year. As most of people belong to poor socioeconomic group, it is essential that cost effective remedial measures must be taken. Moreover judicious use of antimalarials is required to avoid development of resistance. Objective: To determine the frequency of types of malaria and frequency of cases responding to chloroquine as first line treatment in vivax malaria in children of Northern Punjab of Pakistan. Study Design: Descriptive study. Place and Duration of Study: From Jun 2011 to Sept 2012 at Combined Military Hospital Gujranwala in children reporting from surrounding areas both rural and urban with clinical suspicion of malaria. Materials and Methods: During the study period, 175 children were admitted with clinical suspicion of malaria. Out of which 102 were smear positive for malarial parasites, 13 cases were excluded from the study as they lost to follow up, leaving a total of 89 children in the study. Patients under study remained admitted till the fever settled and malarial parasites were negative on smear. Chloroquine was used as first line treatment in cases with vivax malaria. On discharge from hospital, parents of children were advised fortnightly follow up for 28 days. Results: Out of 89 children approx 54% were males and 46% were females. Mean age of participants was 5.91 years. The minimum age was 1 year and maximum 11 years (SD +- 3.09) out of the 89 cases, 84 (94.3%) had vivax malaria, 2 (2.24%) had falciparum malaria and 3 (3.37%) had mixed infection. Our study showed that 79 (94%) cases of vivax malaria fully responded to chloroquine, 5 (6%) cases treated with Chloroquine reported with relapse. Conclusion: Chloroquine is still the drug of choice in vivax malaria. (author)

  15. 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

  16. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia;

    2014-01-01

    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...... 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...... 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...

  19. 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

  20. 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

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

    Directory of Open Access Journals (Sweden)

    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

  2. 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.

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

    OpenAIRE

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

    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 10 6 parasitized erythrocyte suspension in...

  4. 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.......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....

  5. 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...

  6. A FIELD TRIAL ON THE EFFECT OF A COMBINATION OF CYCLOGUANIL PAMOATE AND CHLOROQUINE AGAISNT P. FALCIPARUM

    Directory of Open Access Journals (Sweden)

    A. V. Manouchehri

    1974-09-01

    Full Text Available Cycloguanil Pamoate was intramuscularly injected into semi-immune people living in the hyper-endemic malarias area. The results showed that a single dose of Cycloguanil Pamoate by intramuscular injection together with an oral dose of Chloroquine, 10 mg/kg body weight, suppressed P. falciparum for at least 3 months and P. vivax for 5 months in Bandar abbas, southern Iran.

  7. 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...

  8. 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...

  9. 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.

  10. 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...

  11. 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 ...

  12. 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

  13. 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)

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

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    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.

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

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    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

  16. Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity.

    Science.gov (United States)

    Akpovwa, Hephzibah

    2016-06-01

    Viruses from the Filoviridae family, as many other virus families, require an acidic pH for successful infection and are therefore susceptible to the actions of 4-aminoquinolines, such as chloroquine. Although the mechanisms of action of chloroquine clearly indicate that it might inhibit filoviral infections, several clinical trials that attempted to use chloroquine in the treatment of other acute viral infections - including dengue and influenza A and B - caused by low pH-dependent viruses, have reported that chloroquine had no clinical efficacy, and these results demoted chloroquine from the potential treatments for other virus families requiring low pH for infectivity. The present review is aimed at investigating whether chloroquine could combat the present Ebola virus epidemic, and also at exploring the main reasons for the reported lack of efficacy. Literature was sourced from PubMed, Scopus, Google Scholar, reference list of articles and textbooks - Fields Virology (Volumes 1and 2), the cytokine handbook, Pharmacology in Medicine: Principles and Practice, and hydroxychloroquine and chloroquine retinopathy. The present analysis concludes that (1) chloroquine might find a place in the treatment of Ebola, either as a monotherapy or in combination therapies; (2) the ineffectiveness of chloroquine, or its analogue, hydroxychloroquine, at treating infections from low pH-dependent viruses is a result of the failure to attain and sustain a steady state concentration sufficient to increase and keep the pH of the acidic organelles to approximately neutral levels; (3) to successfully treat filoviral infections - or other viral infections that emerge or emerged from low pH-dependent viruses - a steady state chloroquine plasma concentration of at least 1 µg/mL(~3.125 μM/L) or a whole blood concentration of 16 μM/L must be achieved and be sustained until the patients' viraemia becomes undetectable. These concentrations, however, do not rule out the efficacy of

  17. 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.

  18. Low efficacy of chloroquine: time to switchover to artemisinin-based combination therapy for falciparum malaria in India.

    Science.gov (United States)

    Valecha, N; Joshi, H; Mallick, P K; Sharma, S K; Kumar, A; Tyagi, P K; Shahi, B; Das, M K; Nagpal, B N; Dash, A P

    2009-07-01

    Drug resistance in Plasmodium falciparum poses a major threat to malaria control globally; including India. Chloroquine is still the most widely used drug in the country because of its safety and cost effectiveness. Although chloroquine resistance was first reported in 1973 in North Eastern India, the extent of the problem was realized only after the more intensive 28-day drug efficacy studies were used to monitor drug resistance. In the present study, efficacy of chloroquine in treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures in three distinct epidemiological settings. The prevalence of molecular markers of drug resistance, Pfcrt K76T, Pfmdr1 N86Y, was also studied. A total of 374 children and adults with uncomplicated P. falciparum malaria were enrolled at six sites in four states, treated with chloroquine and follow-up was done for 28 days. The cumulative incidence of success of chloroquine at Day 28 by the Kaplan Meier analysis in the state of Orissa (District Sundargarh, CHC Bisra and Kuarmunda) was 57 (95% CI 43-68) and 54 (95% CI 40-66); in the state of Jharkhand (District Ranchi, PHC Angara and District Simdega, PHC Jaldega) it was 72 (95% CI 59-81) and 65 (95% CI 50-76); in the state of Goa (District North-Goa, Panaji Town), it was 20 (95% CI 10-2) and in the state of Rajasthan (District Udaipur, PHC Rishabdev), it was 96 (95% CI 85-99). Treatment failure was related to Pfcrt mutations but not Pfmdr mutations. Early treatment failure was observed only in 15.8% out of total failures, probably due to the semi-immune nature of the population. This type of response may give false perception about efficacy of the failing drug to patients, clinicians and National Authorities. In a large country like India it is not feasible to conduct in vivo studies in all districts and lack of direct correlation between molecular markers, in vitro studies and treatment outcome makes it difficult to predict

  19. 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.

  20. 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

  1. 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

  2. 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

  3. Influence of oxygen on asexual blood cycle and susceptibility of Plasmodium falciparum to chloroquine: requirement of a standardized in vitro assay

    Directory of Open Access Journals (Sweden)

    Minodier Philippe

    2007-04-01

    Full Text Available Abstract Objective The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodium falciparum growth and 50% inhibitory concentration (IC50 for chloroquine. Methods The study was performed between February 2004 and December 2005. 136 Plasmodium falciparum isolates were used to evaluate gas mixtures effect on IC50 for chloroquine by isotopic microtest. The oxygen effect on asexual blood cycle of 3D7 and W2 clones was determined by thin blood smears examination and tritiated hypoxanthine uptake. Results From 5% O2 to 21% O2 conditions, no parasiticide effect of O2 concentration was observed in vitro on the clones 3D7 and W2. A parasitostatic effect was observed during the exposure of mature trophozoïtes and schizonts at 21% O2 with an increase in the length of schizogony. The chloroquine IC50 at 10% O2 were significantly higher than those at 21% O2, means of 173.5 nM and 121.5 nM respectively (p in vitro resistant to chloroquine (IC50 > 100 nM at 10% O2, 17 were sensitive to chloroquine (IC50 2. Conclusion Based on these results, laboratories should use the same gas mixture to realize isotopic microtest. Further studies on comparison of isotopic and non-isotopic assays are needed to establish a standardized in vitro assay protocol to survey malaria drug resistance.

  4. From chloroquine to artemisinin-based combination therapy: the Sudanese experience

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    Elhassan AH

    2006-07-01

    Full Text Available Abstract Background In Sudan, chloroquine (CQ remains the most frequently used drug for falciparum malaria for more than 40 years. The change to artemisinin-based combination therapy (ACT was initiated in 2004 using the co-blister of artesunate + sulfadoxine/pyrimethamine (AS+SP and artemether + lumefantrine (ART+LUM, as first- and second-line, respectively. This article describes the evidence-base, the process for policy change and it reflects the experience of one year implementation. Relevant published and unpublished documents were reviewed. Data and information obtained were compiled into a structured format. Case description Sudan has used evidence to update its malaria treatment to ACTs. The country moved without interim period and proceeded with country-wide implementation instead of a phased introduction of the new policy. The involvement of care providers and key stakeholders in a form of a technical advisory committee is considered the key issue in the process. Development and distribution of guidelines, training of care providers, communication to the public and provision of drugs were given great consideration. To ensure presence of high quality drugs, a system for post-marketing drugs surveillance was established. Currently, ACTs are chargeable and chiefly available in urban areas. With the input from the Global Fund to fight AIDs, Tuberculosis and Malaria, AS+SP is now available free of charge in 10 states. Conclusion Implementation of the new policy is affected by the limited availability of the drugs, their high cost and limited pre-qualified manufacturers. Substantial funding needs to be mobilized by all partners to increase patients' access for this life-saving intervention.

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

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    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.

  6. 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.

  7. 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. PMID:26001972

  8. Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands.

    Science.gov (United States)

    Ekengard, Erik; Glans, Lotta; Cassells, Irwin; Fogeron, Thibault; Govender, Preshendren; Stringer, Tameryn; Chellan, Prinessa; Lisensky, George C; Hersh, William H; Doverbratt, Isa; Lidin, Sven; de Kock, Carmen; Smith, Peter J; Smith, Gregory S; Nordlander, Ebbe

    2015-11-28

    Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes. PMID:26491831

  9. 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....

  10. 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

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

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    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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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.

  15. 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

  16. Treatment of uncomplicated falciparum malaria in southern Vietnam: can chloroquine or sulfadoxine-pyrimethamine be reintroduced in combination with artesunate?

    Science.gov (United States)

    Nguyen, Mai Huong; Davis, Timothy M E; Cox-Singh, Janet; Hewitt, Sean; Tran, Quoc Toan; Tran, Bach Kim; Nguyen, Thi Hanh; Vo, Nhu Phuong; Doan, Hanh Nhan; Le, Dinh Cong

    2003-12-01

    The effectiveness of chloroquine or sulfadoxine-pyrimethamine administered with artesunate for treating uncomplicated falciparum malaria was assessed in 2 Vietnamese provinces where the sensitivity of parasites in vitro to conventional therapies had increased with the removal of drug pressure. In the province of Dac Lac, where potential malaria exposure begins at birth, 57 subjects (mean age, 9.6 years) were randomized to receive artesunate-chloroquine (group 1) or artesunate-sulfadoxine-pyrimethamine (group 2). In the province of Binh Phuoc, 66 nonimmune workers and their relatives (mean age, 24.2 years) were similarly randomized. By day 28 of follow-up, >96% of Dac Lac patients and Binh Phuoc patients in group 1 and group 2 had an in vivo response that demonstrated sensitivity to therapy. PCR-confirmed cure rates paralleled in vivo results among patients in Binh Phuoc, but PCR results identified 9 (15.7%) of the Dac Lac patients as having experienced asymptomatic, submicroscopic recrudescences. In Dac Lac, pfcrt K76T was near fixation, but infection with parasites with this mutation predicted recrudescence among group 1 patients in Binh Phuoc. Common pfdhfr mutations did not predict outcome in group 2. The successful reintroduction of conventional therapies in combination with artesunate depends on epidemiological and/or parasitological factors. PMID:14614668

  17. 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

  18. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

    International Nuclear Information System (INIS)

    Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU. Our

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

    Directory of Open Access Journals (Sweden)

    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

  20. Soluble Synthetic Analogs of Malaria Pigment: Structure of Mesohematin Anhydride [FeIII(MP-IX)]2 and Solution Interaction with Chloroquine

    Energy Technology Data Exchange (ETDEWEB)

    D Bohle; E Dodd; A Kosar; L Sharma; P Stephens; L Suarez; D Tazoo

    2011-12-31

    Changing the vinyl groups of hematin anhydride to either ethyl or hydrogen groups results in increased solubility (Por=porphyrin). Determination of the weak binding constants of the antimalarial drug chloroquine to dimers of these hematin anhydride analogues suggests that solution-phase heme/drug interactions alone are unlikely to be the origin of the action of the drug.

  1. 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...

  2. 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

    , and therefore a higher toxicity can be expected. The current study examines the pHdependent toxicity and bioaccumulation of the bivalent weak base chloroquine (pKa: 10.47 and 6.33, log KOW 4.67) tested on Salix viminalis (basket willow) and Daphnia magna (water flea). The transpiration rates of hydroponically...

  3. 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

  4. 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....

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. 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.)

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Effects of chloroquine and hepatic stimulator substance on cellular accumulation and nuclear binding of 125I-epidermal growth factor in primary culture of adult rat hepatocytes

    International Nuclear Information System (INIS)

    The effects of chloroquine and hepatic stimulator substance (HSS) on cellular accumulation and nuclear binding of 125I-epidermal growth factor (EGF) were examined in primary culture of adult rat hepatocytes. When intact hepatocytes were incubated at 37 degrees C with 125I-EGF, the cellular accumulation and the nuclear binding reached a peak at 1 h and declined thereafter, where the nuclear binding was 2.49% at 1 h and 2.53% at 2 h. Chloroquine resulted in a time-dependent increase in the cellular accumulation and the nuclear binding was 3.37% at 1 h and 3.72% at 2 h. In contrast, HSS produced no change in each value, suggesting that HSS does not modulate EGF receptors in plasma membrane and nucleus

  10. 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...

  11. 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

  12. 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...

  13. X-ray microanalysis of Plasmodium falciparum and infected red blood cells: effects of qinghaosu and chloroquine on potassium, sodium, and phosphorus composition

    Energy Technology Data Exchange (ETDEWEB)

    Lee, P.; Ye, Z.; Van Dyke, K.; Kirk, R.G.

    1988-08-01

    Cryosections of human red blood cells infected by Plasmodium falciparum were analyzed by energy dispersive x-ray microanalysis to determine the elemental composition of the parasites and their red cell hosts separately. The effects of two antimalarial drugs, qinghaosu and chloroquine, on potassium, sodium, and phosphorus concentrations were studied. Malarial infection causes a decrease in potassium concentration and an increase in sodium concentration in the host red cells. The drastic change in the cation composition, however, occurs only in red cells infected by late stage parasites (late trophozoite and schizont). Red cells infected by early stage parasites (ring stage) show only small changes in sodium concentration. Furthermore, the noninfected red cells in parasitized cultures show no difference in composition from those of normal red cells. Treatment of the parasitized cultures with qinghaosu (10(-6) M) or chloroquine (10(-6) M) for 8 hr causes phosphorus concentration of both early and late parasites to decrease. An 8 hr treatment with qinghaosu also produces a reduction in potassium and an increase in sodium concentrations in early and late parasites. In contrast, 8 hr treatment with chloroquine only causes a change in the sodium and potassium concentrations of the late stage parasites and does not affect the early stage parasites.

  14. 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

  15. 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

  16. 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

  17. Phenotypic reversal of the btn1 defects in yeast by chloroquine: a yeast model for Batten disease.

    Science.gov (United States)

    Pearce, D A; Carr, C J; Das, B; Sherman, F

    1999-09-28

    BTN1 of Saccharomyces cerevisiae encodes an ortholog of CLN3, the human Batten disease gene. We have reported previously that deletion of BTN1, btn1-Delta, resulted in a pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP). This phenotype was caused by btn1-Delta strains having an elevated ability to acidify growth medium through an elevated activity of the plasma membrane H(+)-ATPase, resulting from a decreased vacuolar pH during early growth. We have determined that growing btn1-Delta strains in the presence of chloroquine reverses the resistance to ANP, decreases the rate of medium acidification, decreases the activity of plasma membrane H(+)-ATPase, and elevates vacuolar pH. However, an additional effect of this phenotypic reversal is that activity of plasma membrane H(+)-ATPase is decreased further and vacuolar pH is increased further as btn1-Delta strains continue to grow. This phenotypic reversal of btn1-Delta can be considered for developing a therapy for Batten disease. PMID:10500178

  18. Slow clearance of Plasmodium vivax with chloroquine amongst children younger than six months of age in the Brazilian Amazon

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    André M Siqueira

    2014-08-01

    Full Text Available Plasmodium vivax is the most widespread parasite causing malaria, being especially prevalent in the Americas and Southeast Asia. Children are one of the most affected populations, especially in highly endemic areas. However, there are few studies evaluating the therapeutic response of infants with vivax malaria. This study retrospectively evaluated the parasitaemia clearance in children diagnosed with vivax malaria during the first five days of exclusive treatment with chloroquine (CQ. Infants aged less than six months old had a significantly slower parasitaemia clearance time compared to the group of infants and children between six months and 12 years old (Kaplan-Meier survival analysis; Wilcoxon test; p = 0.004. The impaired clearance of parasitaemia in younger children with vivax malaria is shown for the first time in Latin America. It is speculated that CQ pharmacokinetics in young children with vivax malaria is distinct, but this specific population may also allow the detection of CQ-resistant parasites during follow-up, due to the lack of previous immunity.

  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. 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.

  1. 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.

  2. 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

  3. 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

  4. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century.

    Science.gov (United States)

    Rolain, Jean-Marc; Colson, Philippe; Raoult, Didier

    2007-10-01

    Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide. PMID:17629679

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

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    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 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. PMID:26525783

  6. Killing of Staphylococcus aureus in murine macrophages by chloroquine used alone and in combination with ciprofloxacin or azithromycin

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    Dey S

    2015-01-01

    Full Text Available Somrita Dey, Biswadev BishayiDepartment of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, IndiaAbstract: This study aimed to determine any alteration in the killing of Staphylococcus aureus in murine peritoneal macrophages when chloroquine (CQ is used alone compared with when it is used in combination with ciprofloxacin (CIP or azithromycin (AZM. The study also aimed to find out the implication of reactive oxygen species (ROS production and cytokine release in the intracellular killing of S. aureus in macrophages. We present here data obtained with a model of S. aureus-infected mouse peritoneal macrophages in which the intracellular growth of the bacteria and the influence of antibiotics was monitored for 30, 60, and 90 minutes in the presence or absence of CQ along with the production of ROS and alteration in levels of antioxidant enzymes and cytokines. It was observed that S. aureus-triggered cytokine response was regulated when macrophages were co-cultured with CQ and AZM as compared with CQ stimulation only. It can be suggested that action of AZM in mediating bacterial killing is enhanced by the presence of CQ, indicating enhanced uptake of AZM during early infection that may be essential for bacteria killing by AZM. Reduction of oxidative stress burden on the S. aureus-infected macrophages may pave the way for better killing of internalized S. aureus by CQ plus ciprofloxacin (CIP or CQ plus AZM. Based on these observations, one may speculate that in an inflammatory milieu, CQ loaded with AZM elicits a stronger proinflammatory response by increasing the intracellular uptake of AZM or CIP, thus enabling the immune system to mount a more robust and prolonged response against intracellular pathogens.Keywords: azithromycin, ciprofloxacin, intracellular survival

  7. 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

  8. 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...

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

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    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

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

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    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

  11. Chloroquine Phosphate Oral

    Science.gov (United States)

    ... is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ... on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. ...

  12. 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

  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. 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

    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...... 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...... resistance, CQ alone had a median survival time to parasite clearance equal to that of SP alone (48 h). Parasite clearance by SP was rapid and at the end of 72 h, most (77.3%, 95% confidence interval: 69.6, 85.0) of the children on SP (as a group) had become aparasitaemic. The findings rule out concerns on...

  15. 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...... modulate CQR. To compare patterns of genetic variation at Pfcrt and Pfmdr1 loci, we investigated 460 blood samples from P. falciparum-infected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pfcrt (five loci [approximately 40 kb]) and...... 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....

  16. In vivo sensitivity monitoring of chloroquine for the treatment of uncomplicated vivax malaria in four bordered provinces of Thailand during 2009–2010

    Directory of Open Access Journals (Sweden)

    Kanungnit Congpuong , Wichai Satimai , Anupong Sujariyakul , Somchai Intanakom, Warunee Harnpitakpong , Yuttana Pranuth , Sawad Cholpol & Pongwit Bualombai

    2011-12-01

    Full Text Available Background & objectives: Chloroquine (CQ, followed by 14-day primaquine, is the recommended regimen forthe treatment of Plasmodium vivax infection in Thailand. CQ resistant P. vivax (CRPv has not yet challengedthe efficacy of the drug. The present study was conducted to assess the current response of P. vivax to CQ alonein Thailand.Methods: A 28-day in vivo therapeutic efficacy study was conducted from June 2009 to December 2010 in 4sentinel sites. Recurrence of parasitaemia and the clinical condition of patients were assessed on each visitduring follow-up. The drug levels in recurrent patients’ blood were measured using HPLC. Data were analyzedusing the WHO 2008 program for the analysis of in vivo tests.Results: Of the total 212 patients included in the study, 201 completed the 28-days follow-up, while 11 wereexcluded. In five patients (2.5%, parasitaemia reappeared within the 28-days follow-up. On the day of recurrentparasitaemia, the level of chloroquine/desethylchloroquine (CQ-DCQ was above the minimum effectiveconcentration (>100 ng/ml in one patient, but lower in four patients.Conclusion: Reappearance of the parasite within 28 days of follow-up in one of five patients was due to parasiteresistance to CQ. The 2.5% prevalence of CQ treatment failure for P. vivax malaria in the study areas signals theneed to launch monitoring activities for CQ resistant P. vivax in malaria endemic areas in order to detect furtherdevelopment of parasite resistance and to estimate the level of burden across the country

  17. 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

  18. 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

    OpenAIRE

    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

    2014-01-01

    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 clea...

  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. 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

  1. 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. PMID:26540625

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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

  5. 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

  6. Intérêt comparé de l’imagerie et de l’électrorétinographie multifocale dans le suivi des patients traités par Chloroquine ou Hydroxychloroquine

    OpenAIRE

    Lepoittevin, Maryse

    2015-01-01

    À travers le monde, les antipaludéens de synthèse sont très utilisés dans le traitement préventif et curatif du paludisme ainsi que dans plusieurs pathologies tels que les lupus, polyarthrite rhumatoïde, rhumatismes… Actuellement, en France, environ 40000 patients sont sous antipaludéens de synthèse au long cours, plus de 95 % d’entre eux sont sous hydroxychloroquine et moins de 5 % sous chloroquine. Bien que tous les auteurs confirment le besoin d’une surveillance, il existe une grande varia...

  7. 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)

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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 in......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...

  13. 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

  14. 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

  15. Modification of oxidative status in Plasmodium berghei-infected erythrocytes by E-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl-2'-methyliden]-quinoline compared to chloroquine

    Directory of Open Access Journals (Sweden)

    Juan Rodrigues

    2009-09-01

    Full Text Available E-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl-2'-methyliden]-quinoline (IQ is a new quinoline derivative which has been reported as a haemoglobin degradation and ß-haematin formation inhibitor. The haemoglobin proteolysis induced by Plasmodium parasites represents a source of amino acids and haeme, leading to oxidative stress in infected cells. In this paper, we evaluated oxidative status in Plasmodium berghei-infected erythrocytes in the presence of IQ using chloroquine (CQ as a control. After haemolysis, superoxide dismutase (SOD, catalase, glutathione cycle and NADPH + H+-dependent dehydrogenase enzyme activities were investigated. Lipid peroxidation was also assayed to evaluate lipid damage. The results showed that the overall activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were significantly diminished by IQ (by 53.5% and 100%, respectively. Glutathione peroxidase activity was also lowered (31% in conjunction with a higher GSSG/GSH ratio. As a compensatory response, overall SOD activity increased and lipid peroxidation decreased, protecting the cells from the haemolysis caused by the infection. CQ shared most of the effects showed by IQ; however it was able to inhibit the activity of isocitrate dehydrogenase and glutathione-S-transferase. In conclusion, IQ could be a candidate for further studies in malaria research interfering with the oxidative status in Plasmodium berghei infection.

  16. Reduced Rank Regression

    DEFF Research Database (Denmark)

    Johansen, Søren

    2008-01-01

    The reduced rank regression model is a multivariate regression model with a coefficient matrix with reduced rank. The reduced rank regression algorithm is an estimation procedure, which estimates the reduced rank regression model. It is related to canonical correlations and involves calculating...... eigenvalues and eigenvectors. We give a number of different applications to regression and time series analysis, and show how the reduced rank regression estimator can be derived as a Gaussian maximum likelihood estimator. We briefly mention asymptotic results...

  17. 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

  18. 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.

  19. In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates Avaliação in vitro do verapamil e de outros agentes moduladores em isolados de Plasmodium falciparum resistentes à cloroquina

    Directory of Open Access Journals (Sweden)

    Carla M.S. Menezes

    2003-01-01

    Full Text Available Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility. Intrinsic antiplasmodial activity was observed from the lowest concentrations without a significant modulating action. Other reported modulating agents, such as the antipsychotic drug trifluoperazine and the antidepressants desipramine and imipramine, demonstrated similar responses under the same experimental conditions. Results suggest a much higher susceptibility of Brazilian strains, as well as an indifferent behaviour in relation to modulating agents.Verapamil foi ensaiado quanto ao efeito modulador em isolados brasileiros de Plasmodium falciparum resistentes à cloroquina. Outros agentes cardiovasculares, considerados como moduladores da resistência em malária e/ou em neoplasias multiresistentes a fármacos, como nifedipino, nitrendipino, diltiazem e propranolol foram ensaiados quanto ao mesmo efeito. Concentrações semelhantes às da terapia cardiovascular foram empregadas no ensaio de microtécnica de sensibilidade para fármacos antimaláricos. Atividade antiplasmódica intrínsica foi observada desde as menores concentrações, sem, entretanto, ocorrência de modulação significativa da resistência. Sob as mesmas condições experimentais, respostas semelhantes foram observadas para outros agentes moduladores conhecidos como o antipsicótico trifluoperazina e os antidepressivos desipramina e imipramina. Em conjunto, estes resultados sugerem alta sensibilidade e comportamento indiferente de cepas brasileiras ao efeito de agentes moduladores da resistência.

  20. Reduced protective effect of Plasmodium berghei immunization by concurrent Schistosoma mansoni infection

    Directory of Open Access Journals (Sweden)

    Ramon F Laranjeiras

    2008-11-01

    Full Text Available Studies on concomitant schistosomiasis and human and experimental malaria have shown a variation in the immunospecific response, as well as an increase in the severity of both parasitoses. In the present study, a murine co-infection model was used to determine the effects of a co-infection with Schistosoma mansoni and Plasmodium berghei on the protective immunity acquired by repeated malarial infections and subsequent curative treatment with chloroquine. Our results have demonstrated that, compared to an infection with P. berghei only, the co-infection increases the malarial parasitaemia and decreases the survival rate. Indeed, mice that were immunized by infection and treatment with drug displayed no mortality whereas co-infected mice showed a reduced protective efficacy of immunization against P. berghei (mortality > 60%. Interestingly, this high mortality rate was not associated with high levels of parasitaemia. Our findings support the idea of a suppressive effect of a Schistosoma co-infection on the anti-malarial protection by immunization. This result reveals a possible drawback of the development of anti-malarial vaccines, especially considering the wide endemic areas for both parasitoses.

  1. 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

  2. Pipeline Drag Reducers

    International Nuclear Information System (INIS)

    Pipeline drag reducers have proven to be an extremely powerful tool in fluid transportation. High molecular weight polymers are used to reduce the frictional pressure loss ratio in crude oil pipelines, refined fuel and aqueous pipelines. Chemical structure of the main used pipeline drag reducers is one of the following polymers and copolymers classified according to the type of fluid to ; low density polyethylene, copolymer of I-hexane cross linked with divinyl benzene, polyacrylamide, polyalkylene oxide polymers and their copolymers, fluorocarbons, polyalkyl methacrylates and terpolymer of styrene, alkyl acrylate and acrylic acid. Drag reduction is the increase in pump ability of a fluid caused by the addition of small amounts of an additive to the fluid. The effectiveness of a drag reducer is normally expressed in terms of percent drag reduction. Frictional pressure loss in a pipeline system is a waste of energy and it costly. The drag reducing additive minimizes the flow turbulence, increases throughput and reduces the energy costs. The Flow can be increased by more than 80 % with existing assets. The effectiveness of the injected drag reducer in Mostorod to Tanta crude oil pipeline achieved 35.4 % drag reduction and 23.2 % flow increase of the actual performance The experimental application of DRA on Arab Petroleum Pipeline Company (Summed) achieved a flow increase ranging from 9-32 %

  3. 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.

  4. 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 ...

  5. 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.

  6. Reducing Childhood Obesity

    Science.gov (United States)

    ... Navigation Bar Home Current Issue Past Issues Reducing Childhood Obesity Past Issues / Summer 2007 Table of Contents For ... page please turn Javascript on. The We Can! childhood obesity-prevention program involves parents, caregivers, and community leaders ...

  7. 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.

  8. 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.

  9. Tank closure reducing grout

    International Nuclear Information System (INIS)

    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 Sr90, 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

  10. Reduced Braginskii equations

    International Nuclear Information System (INIS)

    A set of reduced Braginskii equations is derived without assuming flute ordering and the Boussinesq approximation. These model equations conserve the physical energy. It is crucial at finite β that we solve the perpendicular component of Ohm's law to conserve the physical energy while ensuring the relation ∇ · j = 0

  11. 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)\

  12. Reducing conspiracy theory beliefs

    Directory of Open Access Journals (Sweden)

    Stojanov Ana

    2015-01-01

    Full Text Available This study aimed to look at possible ways to reduce beliefs in conspiracy theories and increase the intention to have a fictitious child vaccinated. One hundred and sixty participants answered an online questionnaire. Three groups were used. The control group did not read any text prior to answering whereas the two experimental groups read either only debunking information or information about the motives of the conspiracists and the fallacy in their reasoning in addition to the debunking paragraph. The second experimental manipulation was effective in reducing medical conspiracy theories beliefs, but not belief in conspiracy theories in general. Neither intervention was effective in increasing the likelihood to have a fictitious child vaccinated. Those not intending to vaccinate a fictitious child endorsed conspiracy theories to a greater degree. A positive correlation between beliefs in conspiracy theories and the experiential/intuitive information processing system was found.

  13. 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.

  14. 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

  15. Reducing Children's Media Viewing

    OpenAIRE

    Erin Clyne; Jason, Leonard A.

    2011-01-01

    This case study evaluates the use of a Restrictive aide and the complementary use of parental mediation techniques to reduce media viewing among children. A family was provided a TV Token Timer, which involved a positive reward in exchange for participating in activities outside of watching television. Media viewing habits decreased from the baseline to the completion of the intervention at week 8 for both children. The parent reported high levels of Instructive mediation and positively evalu...

  16. 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...

  17. Reducing conspiracy theory beliefs

    OpenAIRE

    Stojanov Ana

    2015-01-01

    This study aimed to look at possible ways to reduce beliefs in conspiracy theories and increase the intention to have a fictitious child vaccinated. One hundred and sixty participants answered an online questionnaire. Three groups were used. The control group did not read any text prior to answering whereas the two experimental groups read either only debunking information or information about the motives of the conspiracists and the fallacy in their reason...

  18. 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. 

  19. 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.

  20. 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...

  1. 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.

  2. Coating Reduces Ice Adhesion

    Science.gov (United States)

    Smith, Trent; Prince, Michael; DwWeese, Charles; Curtis, Leslie

    2008-01-01

    The Shuttle Ice Liberation Coating (SILC) has been developed to reduce the adhesion of ice to surfaces on the space shuttle. SILC, when coated on a surface (foam, metal, epoxy primer, polymer surfaces), will reduce the adhesion of ice by as much as 90 percent as compared to the corresponding uncoated surface. This innovation is a durable coating that can withstand several cycles of ice growth and removal without loss of anti-adhesion properties. SILC is made of a binder composed of varying weight percents of siloxane(s), ethyl alcohol, ethyl sulfate, isopropyl alcohol, and of fine-particle polytetrafluoroethylene (PTFE). The combination of these components produces a coating with significantly improved weathering characteristics over the siloxane system alone. In some cases, the coating will delay ice formation and can reduce the amount of ice formed. SILC is not an ice prevention coating, but the very high water contact angle (greater than 140 ) causes water to readily run off the surface. This coating was designed for use at temperatures near -170 F (-112 C). Ice adhesion tests performed at temperatures from -170 to 20 F (-112 to -7 C) show that SILC is a very effective ice release coating. SILC can be left as applied (opaque) or buffed off until the surface appears clear. Energy dispersive spectroscopy (EDS) and x-ray photoelectron spectroscopy (XPS) data show that the coating is still present after buffing to transparency. This means SILC can be used to prevent ice adhesion even when coating windows or other objects, or items that require transmission of optical light. Car windshields are kept cleaner and SILC effectively mitigates rain and snow under driving conditions.

  3. 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.

  4. Reducing GWAS Complexity.

    Science.gov (United States)

    Hazelett, Dennis J; Conti, David V; Han, Ying; Al Olama, Ali Amin; Easton, Doug; Eeles, Rosalind A; Kote-Jarai, Zsofia; Haiman, Christopher A; Coetzee, Gerhard A

    2016-01-01

    Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality; we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015 (1,2) from our groups. PMID:26771711

  5. 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

  6. 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.

  7. 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.

  8. 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.)

  9. Cancer Reduces Transcriptome Specialization

    Science.gov (United States)

    Martínez, Octavio; Reyes-Valdés, M. Humberto; Herrera-Estrella, Luis

    2010-01-01

    A central goal of cancer biology is to understand how cells from this family of genetic diseases undergo specific morphological and physiological changes and regress to a de-regulated state of the cell cycle. The fact that tumors are unable to perform most of the specific functions of the original tissue led us to hypothesize that the degree of specialization of the transcriptome of cancerous tissues must be less than their normal counterparts. With the aid of information theory tools, we analyzed four datasets derived from transcriptomes of normal and tumor tissues to quantitatively test the hypothesis that cancer reduces transcriptome specialization. Here, we show that the transcriptional specialization of a tumor is significantly less than the corresponding normal tissue and comparable with the specialization of dedifferentiated embryonic stem cells. Furthermore, we demonstrate that the drop in specialization in cancerous tissues is largely due to a decrease in expression of genes that are highly specific to the normal organ. This approach gives us a better understanding of carcinogenesis and offers new tools for the identification of genes that are highly influential in cancer progression. PMID:20454660

  10. Generalized reduced magnetohydrodynamic equations

    International Nuclear Information System (INIS)

    A new derivation of reduced magnetohydrodynamic (MHD) equations is presented. A multiple-time-scale expansion is employed. It has the advantage of clearly separating the three time scales of the problem associated with (1) MHD equilibrium, (2) fluctuations whose wave vector is aligned perpendicular to the magnetic field, and (3) those aligned parallel to the magnetic field. The derivation is carried out without relying on a large aspect ratio assumption; therefore this model can be applied to any general configuration. By accounting for the MHD equilibrium and constraints to eliminate the fast perpendicular waves, equations are derived to evolve scalar potential quantities on a time scale associated with the parallel wave vector (shear-Alfven wave time scale), which is the time scale of interest for MHD instability studies. Careful attention is given in the derivation to satisfy energy conservation and to have manifestly divergence-free magnetic fields to all orders in the expansion parameter. Additionally, neoclassical closures and equilibrium shear flow effects are easily accounted for in this model. Equations for the inner resistive layer are derived which reproduce the linear ideal and resistive stability criterion of Glasser, Greene, and Johnson. The equations have been programmed into a spectral initial value code and run with shear flow that is consistent with the equilibrium input into the code. Linear results of tearing modes with shear flow are presented which differentiate the effects of shear flow gradients in the layer with the effects of the shear flow decoupling multiple harmonics

  11. 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

  12. 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.

  13. Shrinkage Reducing Admixture for Concrete

    OpenAIRE

    ECT Team, Purdue

    2007-01-01

    Concrete shrinkage cracking is a common problem in all types of concrete structures, especially for structures and environments where the cracks are prevalent and the repercussions are most severe. A liquid shrinkage reducing admixture for concrete, developed by GRACE Construction Products and ARCO Chemical Company, that reduces significantly the shrinkage during concrete drying and potentially reduces overall cracking over time.

  14. 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.

  15. 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...

  16. 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.

  17. 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.

  18. Reducible braids and Garside theory

    CERN Document Server

    Gonzalez-Meneses, Juan

    2010-01-01

    We show that reducible braids which are, in a Garside-theoretical sense, as simple as possible within their conjugacy class, are also as simple as possible in a geometric sense. More precisely, if a braid belongs to a certain subset of its conjugacy class which we call the stabilized set of sliding circuits, and if it is reducible, then its reducibility is geometrically obvious: it has a round or almost round reducing curve. Moreover, for any given braid, an element of its stabilized set of sliding circuits can be found using the well-known cyclic sliding operation. This leads to a polynomial time algorithm for deciding the Nielsen-Thurston type of any braid, modulo one well-known conjecture on the speed of convergence of the cyclic sliding operation.

  19. 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...

  20. Reducing energy with asynchronous circuits

    OpenAIRE

    Rivas Barragan, Daniel

    2012-01-01

    Reducing energy consumption using asynchronous circuits. The elastic clocks approach has been implemented along with a closed-feedback loop in order to achieve a lower energy consumption along with more reliability in integrated circuits.

  1. 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.

  2. 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

  3. 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.

  4. Flexure Bearing Reduces Startup Friction

    Science.gov (United States)

    Clingman, W. Dean

    1991-01-01

    Design concept for ball bearing incorporates small pieces of shim stock, wire spokes like those in bicycle wheels, or other flexing elements to reduce both stiction and friction slope. In flexure bearing, flexing elements placed between outer race of ball bearing and outer ring. Elements flex when ball bearings encounter small frictional-torque "bumps" or even larger ones when bearing balls encounter buildups of grease on inner or outer race. Flexure of elements reduce high friction slopes of "bumps", helping to keep torque between outer ring and inner race low and more nearly constant. Concept intended for bearings in gimbals on laser and/or antenna mirrors.

  5. 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

  6. Reducing ammonia emissions in Europe

    DEFF Research Database (Denmark)

    Jacobsen, Brian H.

    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...... not lived up 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....

  7. Reducing chlorination of niobium pentoxide

    International Nuclear Information System (INIS)

    Studies of cylindric briquettes of Nb2O5 and carbon are presented. The effects of chlorine flow, dimension of the briquettes, porosity, percentage of the reducing agent in the mixture and temperature are analysed. The volatilization aspect of Nb2O5 by the briquettes and the structural transformations of the samples are described. (M.A.C.)

  8. 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

  9. Ways to reduce miner absenteeism

    Energy Technology Data Exchange (ETDEWEB)

    1989-11-01

    Discussion is presented of the use of attendance programs at mines, to reduce interruptions to production, decrease labour costs, and to improve safety. Techniques described include use of absentee charts, frequency of attendance charts, and rewards for good attendance. 3 figs.

  10. 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.

  11. 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…

  12. 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 d...

  13. Reducing Developing Country Debt Reducing Developing Country Debt

    Directory of Open Access Journals (Sweden)

    Paul Krugman

    1989-03-01

    Full Text Available This paper offers a brief primer on the economics of debt reduction for developing countries. It begins by considering the case of unilateral debt forgiveness; such forgiveness is only in the mutual interest of creditors and debtors if the country is on the wrong side of fhe "debt Laffer curve". Current empirical estimafes suggest that problem debtors are in a very flat region of the debt Laffer curve where large changes in face value of debf have only small effcts in expected payments. The paper then considers a variety of market-based debt reduction schemes. It shows that the widespread belief that the markt offers a cheap way to reduce debt is incorrect; unless new market instruments can be made credibly senior to existing debt, debt reductions that impose only small costs to creditors would be very expensive if achieved through buy back. Reducing Developing Country Debt

  14. 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...

  15. 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.

  16. 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.

  17. Reduced graphene oxide molecular sensors.

    Science.gov (United States)

    Robinson, Jeremy T; Perkins, F Keith; Snow, Eric S; Wei, Zhongqing; Sheehan, Paul E

    2008-10-01

    We demonstrate reduced graphene oxide as the active material for high-performance molecular sensors. Sensors are fabricated from exfoliated graphene oxide platelets that are deposited to form an ultrathin continuous network. These graphene oxide networks are tunably reduced toward graphene by varying the exposure time to a hydrazine hydrate vapor. The conductance change of the networks upon exposure to trace levels of vapor is measured as a function of the chemical reduction. The level of reduction affects both the sensitivity and the level of 1/ f noise. The sensors are capable of detecting 10 s exposures to simulants of the three main classes of chemical-warfare agents and an explosive at parts-per-billion concentrations. PMID:18763832

  18. 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.

  19. Structural reducibility of multilayer networks

    Science.gov (United States)

    de Domenico, Manlio; Nicosia, Vincenzo; Arenas, Alexandre; Latora, Vito

    2015-04-01

    Many complex systems can be represented as networks consisting of distinct types of interactions, which can be categorized as links belonging to different layers. For example, a good description of the full protein-protein interactome requires, for some organisms, up to seven distinct network layers, accounting for different genetic and physical interactions, each containing thousands of protein-protein relationships. A fundamental open question is then how many layers are indeed necessary to accurately represent the structure of a multilayered complex system. Here we introduce a method based on quantum theory to reduce the number of layers to a minimum while maximizing the distinguishability between the multilayer network and the corresponding aggregated graph. We validate our approach on synthetic benchmarks and we show that the number of informative layers in some real multilayer networks of protein-genetic interactions, social, economical and transportation systems can be reduced by up to 75%.

  20. 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 ...

  1. 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.

  2. Reducing the addictiveness of cigarettes

    OpenAIRE

    HENNINGFIELD, J.; Benowitz, N.; Slade, J.; Houston, T; DAVIS, R.; Deitchman, S.

    1998-01-01

    OBJECTIVE—To assess the feasibility of reducing tobacco-caused disease by gradually removing nicotine from cigarettes until they would not be effective causes of nicotine addiction.
DATA SOURCES—Issues posed by such an approach, and potential solutions, were identified from analysis of literature published by the US Food and Drug Administration (FDA) in its 1996 Tobacco Rule, comments of the tobacco industry and other institutions and individuals on the rule, review of the reference lists of ...

  3. 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.

  4. 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...

  5. 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

  6. 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....

  7. 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.

  8. 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,

  9. 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

  10. 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...

  11. 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.

  12. The Gambling Reducing Slot Machine

    DEFF Research Database (Denmark)

    Callesen, Mette Buhl; Thomsen, Kristine Rømer; Linnet, Jakob;

    2007-01-01

      The Gambling Reducing Slot Machine - Preliminary results Mette Buhl Callesen, Kristine Rømer Thomsen, Jakob Linnet and Arne Møller The PET Centre, Aarhus University Hospital and Centre of Functionally Integrative Neuroscience, Aarhus, Denmark   Slot machines are among the most addictive forms of...... gambling due to their specific structural characteristics. These include a high event frequency (number of games per minute), a high frequency of small wins and near misses, and auditory as well as visual feedback that reinforce extended gambling behavior [1].   This study focused on gambling behavior in...... pathological gamblers and healthy controls, using one of the most popular slot machines in Denmark, ’Orient Expressen‘. The study included 20 pathological gamblers (10 females) and 20 healthy non-gambling controls (10 females). While being videotaped the subjects played two versions of the slot machine in...

  13. 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. PMID:25125931

  14. 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.

  15. Reduced vibration motor winding arrangement

    Energy Technology Data Exchange (ETDEWEB)

    Slavik, Charles J. (Rexford, NY); Rhudy, Ralph G. (Scotia, NY); Bushman, Ralph E. (Lathem, NY)

    1997-01-01

    An individual phase winding arrangement having a sixty electrical degree phase belt width for use with a three phase motor armature includes a delta connected phase winding portion and a wye connected phase winding portion. Both the delta and wye connected phase winding portions have a thirty electrical degree phase belt width. The delta and wye connected phase winding portions are each formed from a preselected number of individual coils each formed, in turn, from an unequal number of electrical conductor turns in the approximate ratio of .sqroot.3. The individual coils of the delta and wye connected phase winding portions may either be connected in series or parallel. This arrangement provides an armature winding for a three phase motor which retains the benefits of the widely known and utilized thirty degree phase belt concept, including improved mmf waveform and fundamental distribution factor, with consequent reduced vibrations and improved efficiency.

  16. Reduced gravity multibody dynamics testing

    Science.gov (United States)

    Sillanpaa, Meija

    1993-01-01

    The Final Report on reduced gravity multibody dynamics testing is presented. Tests were conducted on board the NASA KC-135 RGA in Houston, Texas. The objective was to analyze the effects of large angle rotations on flexible, multi-segmented structures. The flight experiment was conducted to provide data which will be compared to the data gathered from ground tests of the same configurations. The flight and ground tested data will be used to validate the TREETOPS software, software which models dynamic multibody systems, and other multibody codes. The flight experiment consisted of seven complete flights on board the KC-135 RGA during two one-week periods. The first period of testing was 4-9 Apr. 1993. The second period of testing was 13-18 Jun. 1993.

  17. The ITER reduced cost design

    International Nuclear Information System (INIS)

    Six years of joint work under the international thermonuclear experimental reactor (ITER) EDA agreement yielded a mature design for ITER which met the objectives set for it (ITER final design report (FDR)), together with a corpus of scientific and technological data, large/full scale models or prototypes of key components/systems and progress in understanding which both validated the specific design and are generally applicable to a next step, reactor-oriented tokamak on the road to the development of fusion as an energy source. In response to requests from the parties to explore the scope for addressing ITER's programmatic objective at reduced cost, the study of options for cost reduction has been the main feature of ITER work since summer 1998, using the advances in physics and technology databases, understandings, and tools arising out of the ITER collaboration to date. A joint concept improvement task force drawn from the joint central team and home teams has overseen and co-ordinated studies of the key issues in physics and technology which control the possibility of reducing the overall investment and simultaneously achieving the required objectives. The aim of this task force is to achieve common understandings of these issues and their consequences so as to inform and to influence the best cost-benefit choice, which will attract consensus between the ITER partners. A report to be submitted to the parties by the end of 1999 will present key elements of a specific design of minimum capital investment, with a target cost saving of about 50% the cost of the ITER FDR design, and a restricted number of design variants. Outline conclusions from the work of the task force are presented in terms of physics, operations, and design of the main tokamak systems. Possible implications for the way forward are discussed

  18. 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.

  19. 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

  20. Regulating environments to reduce obesity.

    Science.gov (United States)

    Hayne, Cheryl L; Moran, Patricia A; Ford, Mary M

    2004-01-01

    The marked increase in the prevalence of obesity appears to be attributable to environmental conditions that implicitly discourage physical activity while explicitly encouraging the consumption of greater quantities of energy-dense, low-nutrient foods. In the United States food environment, consumers are bombarded with advertising for unhealthy food, and receive inadequate nutritional information, especially at restaurants. In the US school environment children have access to sugary sodas and unhealthy a la carte foods in their cafeterias, at the same time getting inadequate physical activity and nutrition education. In the built environment, sprawl has reduced active living. We describe these environments and explore the potential effects of regulatory measures on these environments. In the United States, regulatory opportunities exist at the national, state and local levels to mandate action and to allocate funds for promising health-promoting strategies. Regulatory approaches, much like litigation, can transform the entire environment in which corporations operate. Even with incomplete enforcement of rules, they send a public message about what is acceptable behavior for corporations and individuals. Additionally, because the United States is party to many multilateral and bilateral trade agreements and is an active participant in the GATT/WTO framework, US regulatory actions promise to have a beneficial impact both domestically and globally. PMID:15683074

  1. 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

  2. Bioventing reduces soil cleanup costs

    International Nuclear Information System (INIS)

    An offshoot technology from soil venting, bioventing offers a win-win solution for soils contaminated with volatile organic compounds (VOCs) and nonvolatile contaminants such as diesel and fuel oil. Using low air flowrates through permeable soils, bioventing injects sufficient oxygen to support naturally-occurring bacteria, which biodegraded the VOCs and other contaminants into benign byproducts. Waste gas can be directly discharged to atmosphere without further treatment. This results in no offgas treatment required. Bioventing is a cost-effective alternative to traditional soil-venting techniques. Soil venting uses air to volatilize organic-compound contamination from the vadose zone, the unsaturated soil layer above groundwater. Unfortunately, this simple-and-fast approach creates a waste offgas that requires further treatment before discharge, thus adding significantly to overall project costs. In contrast, bioventing uses low air flowrates, which require lower capital and operating costs. No offgas treatment further reduces equipment and operating costs and often eliminates air permitting. As in all treatment strategies, the process must meet the cleanup objectives. Bioventing is an alternative technique making inroads into refining and petrochemical soil-remediation applications

  3. 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。

  4. 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.

  5. 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...

  6. 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...

  7. Microwave Antenna With Reduced Noise Leakage

    Science.gov (United States)

    Cha, A. G.

    1986-01-01

    Gain or gain-to-temperature ratio of dual-shaped subreflector receiving antenna increased when illumination is tapered near aperture edge. Taper imposed in antenna feed reduces spillover in transmitting mode and reduces noise pickup in receiving mode.

  8. 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. 

  9. 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. 

  10. 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...

  11. Characterization of (per)chlorate-reducing bacteria

    OpenAIRE

    Wolterink, A.F.W.M.

    2004-01-01

    Some bacteria can use (per)chlorateas terminal electron acceptor for growth. These bacteria convert perchlorate via chlorate and chlorite into chloride and molecular oxygen. Oxygen formation in microbial respiration is unique. In this study two chlorate-reducing strains belonging to the species Pseudomonas chloritidismutans and a (per)chlorate-reducing strain Dechloromonas hortensis were isolated. The characterization of the chlorate-reducing strain AW-1, which was isolated from a bioreactor ...

  12. 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....

  13. Study on high Tc superconducting ripple reducer

    International Nuclear Information System (INIS)

    This paper presents study on application of high Tc superconductors as a ripple reducer for reduction of the toroidal field (TF) ripple without changing the design of TF coils. The feasibility of the ripple reducer is first demonstrated on the basis of experiments. Next, parameter survey of the ripple reducer is performed for the configuration of the outline design of ITER, and a guideline for the design of the ripple reducer is presented with the consideration of constraints from the technological viewpoint of the fusion reactor. (orig.)

  14. 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...

  15. 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

  16. 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.

  17. Genus Reducing Knots in 3-Manifolds

    OpenAIRE

    Rieck, Yo’av

    2001-01-01

    A genus reducing knot is a knot that has infinitely many surgeries after which the Heegaard genus of the manifold reduces. We study certain aspects of this question, in particular solving it for totally orientable Seifert Fibered Spaces, where we find examples of manifolds of arbitrarily high genus containing no such knot.

  18. A small town reduces its energy expenses

    Energy Technology Data Exchange (ETDEWEB)

    Vissac, G.

    1993-12-31

    Langeac, a 4 300 inhabitants community in France, has relied on its resinous forest and on the local wood industry to save energy, reduce its energy expenses and protect environment. A wood-fired heat network exists, supplied by regional manufacturers. On top of that the charges are reduced in the field of energy. (TEC). 1 fig.

  19. 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…

  20. 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

  1. Welfare Reform and Reducing Teen Pregnancy.

    Science.gov (United States)

    Sawhill, Isabel V.

    2000-01-01

    Most adolescent mothers are unmarried and on welfare. Congress enacted new welfare legislation that emphasizes reducing teen pregnancy and requiring work, but states are reluctant to meet this challenge. Discusses child poverty's new face, public policy and culture wars, welfare reform, and social norms. Concludes that reducing unwed parenthood…

  2. 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.

  3. Soluble calcium amendments: reducing pathogen losses

    Science.gov (United States)

    Flue gas desulfurization (FGD) gypsum is a byproduct of coal-fired power plants. Its application to agricultural fields may increase water infiltration, reduce soil erosion, and decrease nutrient losses from applications of animal manures. It may also reduce fecal bacterial contamination of surface ...

  4. 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

  5. Method and container for reducing pertechnetate

    International Nuclear Information System (INIS)

    A method of reducing the pertechnetate in TcO4- comprises mixing together an aqueous solution of pertechnetate, e.g. the eluant from a technetium generator, metallic tin or an alloy thereof as a reducing agent for the pertechnetate, and a soluble salt of a metal below tin in the electrochemical series, e.g. copper, as an activator for the tin metal reducing agent. A complexing agent for the reduced technetium or a colloid stabiliser may also be included. The pH is preferably 3 to 12. Also claimed is a closed container containing the tin reducing agent, the activator, and the complexant or colloid stabiliser if used, preferably in a freeze-dried sterile state, to which the pertechnetate solution may be added. (author)

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. Reducing nitrogen oxides from power stations

    International Nuclear Information System (INIS)

    The report contains 17 individual lectures of the seminar included in databanks. The lectures concern combustion and waste gas measures for reducing the sulfur dioxide and nitrogen oxide emission from coal-fired and gas-fired power stations. (PW)

  11. 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

  12. 76 FR 6123 - Reducing Regulatory Burden

    Science.gov (United States)

    2011-02-03

    ... Reducing Regulatory Burden AGENCY: Office of the General Counsel, Department of Energy. ACTION: Request for... FURTHER INFORMATION CONTACT: Daniel Cohen, Assistant General Counsel for Legislation, Regulation, and..., the President issued Executive Order 13563, ``Improving Regulation and Regulatory Review,'' to...

  13. 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)

  14. 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.

  15. 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.

  16. Goal directed fluid therapy reduces major

    Directory of Open Access Journals (Sweden)

    Dina Y. Kassim

    2016-04-01

    Conclusion: A restrictive strategy of fluid maintenance during optimization of oxygen delivery with early treatment directed to maintain oxygen extraction ratio estimate (O2ERe at <27% reduces major complications and hospital stay of surgical patients undergo abdominal aortic aneurysm.

  17. 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

  18. Deep brain stimulation to reduce sexual drive

    Science.gov (United States)

    Fuss, Johannes; Auer, Matthias K.; Biedermann, Sarah V.; Briken, Peer; Hacke, Werner

    2015-01-01

    To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID:26057198

  19. 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.

  20. How Stress Can Reduce Dissipation in Glasses

    OpenAIRE

    Wu, Jiansheng; Yu, Clare C.

    2011-01-01

    We propose that stress can decrease the internal friction of amorphous solids, either by increasing the potential barriers of defects, thus reducing their tunneling and thermal activation that produce loss, or by decreasing the coupling between defects and phonons. This stress can be from impurities, atomic bonding constraints, or externally applied stress. Externally applied stress also reduces mechanical loss through dissipation dilution. Our results are consistent with the experiments, and...

  1. 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.

  2. 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...

  3. 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.

  4. Reducing stereotype threat by blurring intergroup boundaries.

    OpenAIRE

    Rosenthal, H. E. S.; Crisp, R. J.

    2006-01-01

    The authors aimed to establish whether interventions designed to reduce intergroup bias could be applied to the stereotype threat domain. In three experiments, the hypothesis was tested that blurring intergroup boundaries would reduce stereotype threat. In the first study, it was found that female participants who thought about characteristics shared between the genders tended to show less preference for stereotypical female careers than did participants in the baseline condition. In. Experim...

  5. 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...

  6. 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...

  7. Reduced form of a Mueller matrix

    OpenAIRE

    Gil, Jose J.; Jose, Ignacio San

    2015-01-01

    Through a simple procedure based on the Lu-Chipman decomposition [S-Y. Lu and R. C. Chipman, J. Opt. Soc. Am A 13, 1106 (1996)] any depolarizing Mueller matrix can be transformed into a reduced form which accumulates the depolarization and polarizance properties into a set of six parameters. The simple structure of this reduced form provides straightforward ways for the general characterization of Mueller matrices as well as for the analysis of singular Mueller matrices.

  8. Reduced form of a Mueller matrix

    CERN Document Server

    Gil, Jose J

    2015-01-01

    Through a simple procedure based on the Lu-Chipman decomposition [S-Y. Lu and R. C. Chipman, J. Opt. Soc. Am A 13, 1106 (1996)] any depolarizing Mueller matrix can be transformed into a reduced form which accumulates the depolarization and polarizance properties into a set of seven parameters. The simple structure of this reduced form provides straightforward ways for the general characterization of Mueller matrices as well as for the analysis of singular Mueller matrices.

  9. 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

  10. A Reducing Resistance to Change Model

    OpenAIRE

    Daniela Braduţanu

    2015-01-01

    The aim of this scientific paper is to present an original reducing resistance to change model. After analyzing the existent literature, I have concluded that the resistance to change subject has gained popularity over the years, but there are not too many models that could help managers implement more smoothly an organizational change process and at the same time, reduce effectively employees’ resistance. The proposed model is very helpful for managers and change agents who are c...

  11. Multiple polylogarithms and linearly reducible Feynman graphs

    CERN Document Server

    Bogner, Christian

    2013-01-01

    We review an approach for the computation of Feynman integrals by use of multiple polylogarithms, with an emphasis on the related criterion of linear reducibility of the graph. We show that the set of graphs which satisfies the linear reducibility with respect to both Symanzik polynomials is closed under taking minors. As a step towards a classification of Feynman integrals, we discuss the concept of critical minors and exhibit an example at three loops with four on-shell legs.

  12. 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, ...

  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. Biplots in Reduced-Rank Regression

    OpenAIRE

    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 components analysis and can therefore be carried out with standard statistical packages. The proposed biplot highlights the major aspects of the regressions by displaying the least-squares approxima...

  15. Reduced waste generation technical work plan

    International Nuclear Information System (INIS)

    The United States Department of Energy has established policies for avoiding plutonium losses to the waste streams and minimizing the generation of wastes produced at its nuclear facilities. This policy is evidenced in DOE Order 5820.2, which states ''Technical and administrative controls shall be directed towards reducing the gross volume of TRU waste generated and the amount of radioactivity in such waste.'' To comply with the DOE directive, the Defense Transuranic Waste Program (DTWP) supports and provides funding for specific research and development tasks at the various DOE sites to reduce the generation of waste. This document has been prepared to give an overview of current and past Reduced Waste Generation task activities which are to be based on technical and cost/benefit factors. The document is updated annually, or as needed, to reflect the status of program direction. Reduced Waste Generation (RWG) tasks encompass a wide range of goals which are basically oriented toward (1) avoiding the generation of waste, (2) changing processes or operations to reduce waste, (3) converting TRU waste into LLW by sorting or decontamination, and (4) reducing volumes through operations such as incineration or compaction

  16. 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.

  17. Evolution of technetium speciation in reducing grout

    International Nuclear Information System (INIS)

    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

  18. 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

  19. Understanding Uranium Behavior in a Reduced Aquifer

    Science.gov (United States)

    Janot, N.; Lezama-Pacheco, J. S.; Williams, K. H.; Bernier-Latmani, R.; Long, P. E.; Davis, J. A.; Fox, P. M.; Yang, L.; Giammar, D.; Cerrato, J. M.; Bargar, J.

    2012-12-01

    Uranium contamination of groundwater is a concern at several US Department of Energy sites, such Old Rifle, CO. Uranium transport in the environment is mainly controlled by its oxidation state, since oxidized U(VI) is relatively mobile, whereas U(IV) is relatively insoluble. Bio-remediation of contaminated aquifers aims at immobilizing uranium in a reduced form. Previous laboratory and field studies have shown that adding electron donor (lactate, acetate, ethanol) to groundwater stimulates the activity of metal- and sulfate-reducing bacteria, which promotes U(VI) reduction in contaminated aquifers. However, obtaining information on chemical and physical forms of U, Fe and S species for sediments biostimulated in the field, as well as kinetic parameters such as U(VI) reduction rate, is challenging due to the low concentration of uranium in the aquifers (typically bio-remediation experiment at the Old Rifle site, CO, from early iron-reducing conditions to the transition to sulfate-reducing conditions. Several in-well chromatographic columns packed with sediment were deployed and were sampled at different days after the start of bio-reduction. X-ray absorption spectroscopy and X-ray microscopy were used to obtain information on Fe, S and U speciation and distribution. Chemical extractions of the reduced sediments have also been performed, to determine the rate of Fe(II) and U(IV) accumulation.

  20. 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

  1. 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.

  2. Local stressors reduce coral resilience to bleaching.

    Directory of Open Access Journals (Sweden)

    Jessica E Carilli

    Full Text Available Coral bleaching, during which corals lose their symbiotic dinoflagellates, typically corresponds with periods of intense heat stress, and appears to be increasing in frequency and geographic extent as the climate warms. A fundamental question in coral reef ecology is whether chronic local stress reduces coral resistance and resilience from episodic stress such as bleaching, or alternatively promotes acclimatization, potentially increasing resistance and resilience. Here we show that following a major bleaching event, Montastraea faveolata coral growth rates at sites with higher local anthropogenic stressors remained suppressed for at least 8 years, while coral growth rates at sites with lower stress recovered in 2-3 years. Instead of promoting acclimatization, our data indicate that background stress reduces coral fitness and resilience to episodic events. We also suggest that reducing chronic stress through local coral reef management efforts may increase coral resilience to global climate change.

  3. 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.

  4. 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. PMID:24320065

  5. Outcomes of a program to reduce depression.

    Science.gov (United States)

    Kim, Gyung Hee; Kim, Kyeha; Park, Hyojung

    2011-06-01

    Depression is increasing among Korean college students. Moreover, it is common for depressed individuals to consider attempting suicide. The purpose of this study therefore was to develop and examine the effectiveness of an intervention to reduce suicidal ideation and depression among female college students. Study participants were assigned to either an intervention (n = 27) or control (n = 31) group. The intervention group received a depression-reducing program in eight 1-hr weekly sessions. Measures of suicidal ideation and depression were administered. The program has effects on suicidal ideation and depression among female college students. The findings suggest that the study program may be useful in reducing suicidal ideation and depression among female college students. PMID:21078916

  6. 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.

  7. 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

  8. 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.

  9. 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...

  10. Does Formal Employment Reduce Informal Caregiving?

    Science.gov (United States)

    He, Daifeng; McHenry, Peter

    2016-07-01

    Using the Survey of Income and Program Participation, we examine the impact of formal employment on informal caregiving. We instrument for individual work hours with state unemployment rates. We find that, among women of prime caregiving ages (40-64 years), working 10% more hours per week reduces the probability of providing informal care by about 2 percentage points. The effects are stronger for more time-intensive caregiving and if care recipients are household members. Our results imply that work-promoting policies have the unintended consequence of reducing informal caregiving in an aging society. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26017375

  11. 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.

  12. Formal derivation of distributed MapReduce

    OpenAIRE

    Pereverzeva, Inna; Butler, Michael; Salehi Fathabadi, Asieh; Laibinis, Linas; Troubitsyna, Elena

    2014-01-01

    MapReduce is a powerful distributed data processing model that is currently adopted in a wide range of domains to efficiently handle large volumes of data, i.e., cope with the big data surge. In this paper, we propose an approach to formal derivation of the MapReduce framework. Our approach relies on stepwise refinement in Event-B and, in particu- lar, the event refinement structure approach – a diagrammatic notation facilitating formal development. Our approach allows us to derive the system...

  13. 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.

  14. 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.

  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. 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...

  17. Reducing Abstraction When Learning Graph Theory

    Science.gov (United States)

    Hazzan, Orit; Hadar, Irit

    2005-01-01

    This article presents research on students' understanding of basic concepts in Graph Theory. Students' understanding is analyzed through the lens of the theoretical framework of reducing abstraction (Hazzan, 1999). As it turns out, in spite of the relative simplicity of the concepts that are introduced in the introductory part of a traditional…

  18. 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.

  19. Engaging to reduce emissions and solidarity

    International Nuclear Information System (INIS)

    The different negotiations about the reduction of greenhouse gases emissions is studied in this article. The problem of developing countries or fast developing countries such asian countries is evoked. The rate of carbon dioxide emission could be calculated in function of GDP (gross domestic product) to allow to reduce the gaps between the different countries. (N.C.)

  20. 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

  1. 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

  2. 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...

  3. Clinker mineral hydration at reduced relative humidities

    DEFF Research Database (Denmark)

    Jensen, Ole Mejlhede; Hansen, Per Freiesleben; Lachowski, Eric E.; Glasser, Fred P.

    1999-01-01

    Vapour phase hydration of purl cement clinker minerals at reduced relative humidities is described. This is relevant to modern high performance concrete that may self-desiccate during hydration and is also relevant to the quality of the cement during storage. Both the oretical considerations and...

  4. 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…

  5. 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…

  6. 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)

  7. 77 FR 31548 - Reducing Regulatory Burden

    Science.gov (United States)

    2012-05-29

    ...; ] DEPARTMENT OF ENERGY 5 CFR Chapter XXII 10 CFR Chapters II, III, X Reducing Regulatory Burden AGENCY: Office... Regulation and Regulatory Review,'' is extended to June 19, 2012. DATES: DOE will accept comments, data, and... INFORMATION CONTACT: Daniel Cohen, Assistant General Counsel for Legislation, Regulation, and...

  8. 77 FR 28518 - Reducing Regulatory Burden

    Science.gov (United States)

    2012-05-15

    ...; ] DEPARTMENT OF ENERGY 5 CFR Chapter XXII 10 CFR Chapters II, III, X Reducing Regulatory Burden AGENCY: Office... its implementation of Executive Order 13563, ``Improving Regulation and Regulatory Review,'' issued by... INFORMATION CONTACT: Daniel Cohen, Assistant General Counsel for Legislation, Regulation, and...

  9. 77 FR 47328 - Reducing Regulatory Burden

    Science.gov (United States)

    2012-08-08

    ...; ] DEPARTMENT OF ENERGY 5 CFR Chapter XXII 10 CFR Chapters II, III, X Reducing Regulatory Burden AGENCY: Office... its implementation of Executive Order 13563, ``Improving Regulation and Regulatory Review,'' issued by... . FOR FURTHER INFORMATION CONTACT: Daniel Cohen, Assistant General Counsel for Legislation,...

  10. 76 FR 75798 - Reducing Regulatory Burden

    Science.gov (United States)

    2011-12-05

    ...; ] DEPARTMENT OF ENERGY 5 CFR Chapter XXIII 10 CFR Chapters II, III, X Reducing Regulatory Burden AGENCY: Office... its implementation of Executive Order 13563, ``Improving Regulation and Regulatory Review,'' issued by... General Counsel for Legislation, Regulation, and Energy Efficiency, U.S. Department of Energy, Office...

  11. 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.

  12. On reduced density matrices for disjoint subsystems

    Science.gov (United States)

    Iglói, F.; Peschel, I.

    2010-02-01

    We show that spin and fermion representations for solvable quantum chains lead in general to different reduced density matrices if the subsystem is not singly connected. We study the effect for two sites in XX and XY chains as well as for sublattices in XX and transverse Ising chains.

  13. 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…

  14. Reducing Mathematics Anxiety with Computer Assisted Instruction.

    Science.gov (United States)

    Harris, Albert L.; Harris, Jacqueline M.

    1987-01-01

    Student, teacher, and teaching causes of mathematics anxiety are discussed. Computer-assisted instruction can reduce mathematics anxieties due to lack of confidence, negative attitudes, teacher bias, authoritarian teaching, lack of variety, lack of relationship with the real world, emphasis on memorization or on speed, or computer phobia. (MNS)

  15. Vitamin D with Calcium Reduces Mortality

    DEFF Research Database (Denmark)

    Rejnmark, Lars; Avenell, Alison; Masud, Tahir;

    2012-01-01

    ,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin...... D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus...... calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06).Conclusion:Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone....

  16. 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…

  17. Involutions and Representations for Reduced Quantum Algebras

    CERN Document Server

    Gutt, Simone

    2009-01-01

    In the context of deformation quantization, there exist various procedures to deal with the quantization of a reduced space M_red. We shall be concerned here mainly with the classical Marsden-Weinstein reduction, assuming that we have a proper action of a Lie group G on a Poisson manifold M, with a moment map J for which zero is a regular value. For the quantization, we follow [BHW] (with a simplified approach) and build a star product *_red on M_red from a strongly invariant star product * on M. The new questions which are addressed in this paper concern the existence of natural *-involutions on the reduced quantum algebra and the representation theory for such a reduced *-algebra. We assume that * is Hermitian and we show that the choice of a formal series of smooth densities on the embedded coisotropic submanifold C = J^{-1}(0), with some equivariance property, defines a *-involution for *_red on the reduced space. Looking into the question whether the corresponding *-involution is the complex conjugation ...

  18. 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…

  19. 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.

  20. 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.

  1. 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…

  2. 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

  3. 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)

  4. 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.

  5. A reduced gravity fiber pulling apparatus

    Science.gov (United States)

    Tucker, D. S.

    1992-01-01

    A reduced gravity fiber pulling apparatus (FPA) was constructed in order to study the effects of gravity on glass fiber formation. The apparatus was specifically designed and built for use on NASA's KC-135 aircraft. To date, four flights have been completed during which E-glass fiber was successfully produced in simulated lunar gravity.

  6. 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.

  7. Reduced alphabet for protein folding prediction.

    Science.gov (United States)

    Huang, Jitao T; Wang, Titi; Huang, Shanran R; Li, Xin

    2015-04-01

    What are the key building blocks that would have been needed to construct complex protein folds? This is an important issue for understanding protein folding mechanism and guiding de novo protein design. Twenty naturally occurring amino acids and eight secondary structures consist of a 28-letter alphabet to determine folding kinetics and mechanism. Here we predict folding kinetic rates of proteins from many reduced alphabets. We find that a reduced alphabet of 10 letters achieves good correlation with folding rates, close to the one achieved by full 28-letter alphabet. Many other reduced alphabets are not significantly correlated to folding rates. The finding suggests that not all amino acids and secondary structures are equally important for protein folding. The foldable sequence of a protein could be designed using at least 10 folding units, which can either promote or inhibit protein folding. Reducing alphabet cardinality without losing key folding kinetic information opens the door to potentially faster machine learning and data mining applications in protein structure prediction, sequence alignment and protein design. PMID:25641420

  8. Identifying and reducing constraints to potato productivity

    Science.gov (United States)

    Potato yield in Maine has remained relatively constant for over 50 years, despite increased inputs of pesticides, nutrients, and water. Research is needed to identify and reduce the constraints to potato productivity. We evaluated Status Quo, Soil Conserving, Soil Improving, and Disease Suppressive ...

  9. 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…

  10. 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…

  11. 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…

  12. 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.

  13. 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.

  14. 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,…

  15. 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.

  16. Penerapan Reduced Impact Logging Menggunakan Monocable Winch (Pancang Tarik) (Implementing Reduced Impact Logging with Monocable Winch)

    OpenAIRE

    Yosep Ruslim

    2012-01-01

    Forest harvesting still encounters many problems especially concerning impact to the residual stand  and environmental damage. Implementing the reduced impact monocable winch and planning of good skid trails should have a positive impact on work efficiency as well as, reducing damage to the residual stand and soil during felling and skidding activities. Reduced impact logging (RIL) with a monocable winch (Pancang Tarik) system has been tried in several IUPHHKs and it can be concluded that RIL...

  17. 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

  18. Reducing Tariffs According to WTO Accession Rules

    DEFF Research Database (Denmark)

    Fosse, Henrik Barslund; Raimondos-Møller, Pascalis

    2012-01-01

    When Vietnam joined the World Trade Organization (WTO) in 2007 it was granted an accession period up to 2014. During this period tariffs would have to fall according to the accession agreement. This paper evaluates this 2007–2014 trade liberalization by building an applied general equilibrium model...... and calibrating it to the Vietnamese data. The model pays careful attention to the fact that Vietnam has many state-owned enterprises. The model simulations show that the WTO tariff reductions will reduce overall welfare. Moreover, the biggest loss will take place among the poor rural households in...... Vietnam. This paper proposes other tariff reforms that will both raise overall welfare and reduce income inequality....

  19. Reducing CQI Signalling Overhead in HSPA

    Directory of Open Access Journals (Sweden)

    Saied M. Abd El-atty

    2008-01-01

    Full Text Available The efficiency of adaptive modulation and coding (AMC procedure in high speed Downlink packet access (HSDPA depends on the frequency of the channel quality information (CQI reports transmitted by the UE to Node B. The more frequent the reports are the more accurate the link adaptation procedure is. On the other hand, the frequent CQI reports increase uplink interference, reducing thus the signal reception quality at the uplink. In this study, we propose an improved CQI reporting scheme which aims to reduce the required CQI signaling by exploiting a CQI prediction method based on a finite-state Markov chain (FSMC model of the wireless channel. The simulation results show that under a high downlink traffic load, the proposed scheme has a near-to-optimum performance while produces less interference compared to the respective periodic CQI scheme.

  20. 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...

  1. 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

  2. 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...

  3. 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.

  4. 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.

  5. 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

  6. Producing Knowledge to Reduce Rhetorical Distance

    DEFF Research Database (Denmark)

    Kampf, Constance

    foot, the radio an extension of the ear, the television an extension of the eye. From this perspective, exploring the internet as an extension of identity produces fruitful questions about the role of on-line writing in Web presences. The Web changes writing as a knowledge-making practice by offering......Producing Knowledge to Reduce Rhetorical Distance: Extending Identity and Engaging Mainstream Ideology via the Web Constance Kampf, Department of Research Knowledge Communication, Aarhus School of Business, Denmark McLuhan describes technologies as extensions -the wheel being an extension of the...... writers a larger public forum into which they can extend their identity. When the identity being extended represents a minority group, the web offers an opportunity for members of that group to engage mainstream ideology and work at reducing the rhetorical distance between their identity and mainstream...

  7. Countermeasures for Reducing Alcohol-Related Crashes.

    Science.gov (United States)

    Voas, R B

    2000-01-01

    Programs to prevent alcohol-related crashes occur at several levels. Although most of the public thinks of drunk-driving prevention only in terms of the criminal justice system, much can be done to prevent alcohol-related highway deaths before the drinking-and-driving offender gets on the road. In recent years, the field of alcohol safety has merged with the area of public health concerned with preventing alcohol- and drug-related traumatic injury and death. This paper provides an overview of the status of road safety programs directed at reducing impaired driving. It covers ten topics falling into the three levels of prevention: primary programs to reduce alcohol consumption; secondary programs to prevent driving after drinking; and tertiary programs to prevent recidivism among convicted drinking drivers. PMID:26256029

  8. 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...

  9. FETC Programs for Reducing Greenhouse Gas Emissions

    International Nuclear Information System (INIS)

    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

  10. 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

  11. Direct reducing method for metal ore

    International Nuclear Information System (INIS)

    In a high temperature steam electrolysis device using solid electrolyte, a hydrogen gas is generated from steams by using nuclear heat at high temperature from a high temperature gas cooling reactor (HTGR) and electric power generated by the nuclear temperature, to directly reduce metal ores by the hydrogen gas. With such procedures, no CO2 is evolved. Further, steams in a gas mixture of the hydrogen gas and the steams generated from the high temperature steam electrolysis device are adsorbed by a pressure swing type (PSA) steam adsorbing device to be separated from the hydrogen gas. Metal ores are directly reduced by the hydrogen gas separated from steams. With such procedures, since the steams are adsorbed and separated from hydrogen gas in the PSA without condensation, it is possible to reutilize separated steams as a heat source, thereby enabling to improve thermal efficiency. (T.M.)

  12. 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

  13. 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...

  14. A Reducing Resistance to Change Model

    Directory of Open Access Journals (Sweden)

    Daniela Braduţanu

    2015-10-01

    Full Text Available The aim of this scientific paper is to present an original reducing resistance to change model. After analyzing the existent literature, I have concluded that the resistance to change subject has gained popularity over the years, but there are not too many models that could help managers implement more smoothly an organizational change process and at the same time, reduce effectively employees’ resistance. The proposed model is very helpful for managers and change agents who are confronted with a high degree of resistance when trying to implement a new change, as well as for researches. The key contribution of this paper is that resistance is not necessarily bad and if used appropriately, it can actually represent an asset. Managers must use employees’ resistance.

  15. 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

  16. Distraction from emotional information reduces biased judgements.

    Science.gov (United States)

    Lench, Heather C; Bench, Shane W; Davis, Elizabeth L

    2016-06-01

    Biases arising from emotional processes are some of the most robust behavioural effects in the social sciences. The goal of this investigation was to examine the extent to which the emotion regulation strategy of distraction could reduce biases in judgement known to result from emotional information. Study 1 explored lay views regarding whether distraction is an effective strategy to improve decision-making and revealed that participants did not endorse this strategy. Studies 2-5 focused on several established, robust biases that result from emotional information: loss aversion, desirability bias, risk aversion and optimistic bias. Participants were prompted to divert attention away from their feelings while making judgements, and in each study this distraction strategy resulted in reduced bias in judgement relative to control conditions. The findings provide evidence that distraction can improve choice across several situations that typically elicit robustly biased responses, even though participants are not aware of the effectiveness of this strategy. PMID:25787937

  17. 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.

  18. 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.

  19. Advanced technology for reducing aircraft engine pollution

    Science.gov (United States)

    Jones, R. E.

    1973-01-01

    The proposed EPA regulations covering emissions of gas turbine engines will require extensive combustor development. The NASA is working to develop technology to meet these goals through a wide variety of combustor research programs conducted in-house, by contract, and by university grant. In-house efforts using the swirl-can modular combustor have demonstrated sizable reduction in NO emission levels. Testing to reduce idle pollutants has included the modification of duplex fuel nozzles to air-assisted nozzles and an exploration of the potential improvements possible with combustors using fuel staging and variable geometry. The Experimental Clean Combustor Program, a large contracted effort, is devoted to the testing and development of combustor concepts designed to achieve a large reduction in the levels of all emissions. This effort is planned to be conducted in three phases with the final phase to be an engine demonstration of the best reduced emission concepts.

  20. 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.

  1. 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...

  2. 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

  3. Pyruvate reduces 4-aminophenol in vitro toxicity

    International Nuclear Information System (INIS)

    Pyruvate has been observed to reduce the nephrotoxicity of some agents by maintaining glutathione status and preventing lipid peroxidation. This study examined the mechanism for pyruvate protection of p-aminophenol (PAP) nephrotoxicity. Renal cortical slices from male Fischer 344 rats were incubated for 30-120 min with 0, 0.1, 0.25 or 0.5 mM PAP in oxygenated Krebs buffer containing 0 or 10 mM pyruvate or glucose (1.28 or 5.5 mM). LDH leakage was increased above control by 0.25 and 0.5 mM PAP beginning at 60 min and by 0.1 mM PAP at 120 min. Pyruvate prevented an increase in LDH leakage at 60- and 120-min exposure to 0.1 and 0.25 mM PAP. Pyruvate also prevented a decline in ATP levels. Glucose (1.28 and 5.5 mM) provided less protection than pyruvate from PAP toxicity. Total glutathione levels were diminished by 0.1 and 0.25 mM PAP within 60 and 30 min, respectively. Pyruvate prevented the decline in glutathione by 0.1 mM PAP at both time periods and at 30 min for 0.25 mM PAP. Pyruvate reduced the magnitude of glutathione depletion by 0.25 mM PAP following a 60-min incubation. Glutathione disulfide (GSSG) levels in renal slices were increased at 60 min by exposure to 0.25 mM PAP, while pyruvate prevented increased GSSG levels by PAP. Pyruvate also reduced the extent of 4-hydroxynonenal (4-HNE)-adducted proteins present after a 90-min incubation with PAP. These results indicate that pyruvate provided protection for PAP toxicity by providing an energy substrate and reducing oxidative stress

  4. 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...

  5. Tail Rotor Airfoils Stabilize Helicopters, Reduce Noise

    Science.gov (United States)

    2010-01-01

    Founded by former Ames Research Center engineer Jim Van Horn, Van Horn Aviation of Tempe, Arizona, built upon a Langley Research Center airfoil design to create a high performance aftermarket tail rotor for the popular Bell 206 helicopter. The highly durable rotor has a lifetime twice that of the original equipment manufacturer blade, reduces noise by 40 percent, and displays enhanced performance at high altitudes. These improvements benefit helicopter performance for law enforcement, military training, wildfire and pipeline patrols, and emergency medical services.

  6. 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.

  7. 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 ...

  8. 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

  9. 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

  10. Reduced Variation in Drosophila Simulans Mitochondrial DNA

    OpenAIRE

    Ballard, JWO.; Hatzidakis, J.; Karr, T L; Kreitman, M

    1996-01-01

    We investigated the evolutionary dynamics of infection of a Drosophila simulans population by a maternally inherited insect bacterial parasite, Wolbachia, by analyzing nucleotide variability in three regions of the mitochondrial genome in four infected and 35 uninfected lines. Mitochondrial variability is significantly reduced compared to a noncoding region of a nuclear-encoded gene in both uninfected and pooled samples of flies, indicating a sweep of genetic variation. The selective sweep of...

  11. 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 $(w \\leq 1)$.

  12. Natural Supersymmetry From Dynamically Reduced Radiative Correction

    CERN Document Server

    Han, Huayong

    2015-01-01

    New natural supersymmetry is explored in the light of dynamically reduced radiative correction. Unlike in the conventional natural supersymmetry, the range of supersymmetric mass spectrum can be far above the TeV scale instead. For the illustrating model of non-universal gaugino masses, the parameter space which satisfies the Higgs mass and other LHC constraints is shown explicitly. We propose that this example can be realized by employing the no-scale supergravity.

  13. 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...

  14. 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...

  15. Reducing the Genotoxic Potential of Retroviral Vectors

    OpenAIRE

    Ramezani, Ali; Hawley, Teresa S.; Hawley, Robert G.

    2008-01-01

    The recent development of leukemia in gene therapy patients with X-linked severe combined immunodeficiency disease due to retroviral vector insertional mutagenesis has prompted reassessment of the genotoxic potential of integrating vector systems. In this chapter, various strategies are described to reduce the associated risks of retroviral genomic integration. These include deletion of strong transcriptional enhancer-promoter elements in the retroviral long terminal repeats, flanking the ret...

  16. Customized notched music training reduces tinnitus loudness

    OpenAIRE

    Stracke, Henning; Okamoto, Hidehiko; Pantev, Christo

    2010-01-01

    Chronic tinnitus is a symptom with high prevalence. There is evidence that the tinnitus perception is related to unfavorable cortical plastic changes. In our recent study we have developed and evaluated a customized music training strategy that appears capable of both reducing cortical tinnitus related neuronal activity and alleviating subjective tinnitus perception. We hypothesize that the regular and enjoyable music training reverses unprofitable cortical reorganization to a certain degree ...

  17. Local Stressors Reduce Coral Resilience to Bleaching

    OpenAIRE

    Carilli, Jessica E; Norris, Richard D.; Black, Bryan A.; Walsh, Sheila M.; McField, Melanie

    2009-01-01

    Coral bleaching, during which corals lose their symbiotic dinoflagellates, typically corresponds with periods of intense heat stress, and appears to be increasing in frequency and geographic extent as the climate warms. A fundamental question in coral reef ecology is whether chronic local stress reduces coral resistance and resilience from episodic stress such as bleaching, or alternatively promotes acclimatization, potentially increasing resistance and resilience. Here we show that following...

  18. 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...

  19. 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

  20. Glucocorticoids reduce phobic fear in humans

    OpenAIRE

    Soravia, Leila M; Heinrichs, Markus; Aerni, Amanda; Maroni, Caroline; Schelling, Gustav; Ehlert, Ulrike; Roozendaal, Benno; de Quervain, Dominique J.-F.

    2006-01-01

    Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fea...

  1. Reducing Complexity and Consumption in Future Networks

    Directory of Open Access Journals (Sweden)

    G. M. Tosi Beleffi

    2010-11-01

    Full Text Available The authors report the main results of the EU FP7 SARDANA project, a future network architecture able to provide large bandwidth to the end user in a flexible and intelligent way. The remote amplification for network reach extension, the remote monitoring of the network infrastructure, and the possibility of remotely powering ONUs are fundamental capabilities to maintain the passiveness of the network outside plant, so important for reducing power consumption and maintenance costs, without compromising network reach and coverage.

  2. 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...

  3. 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...

  4. A proportional counter with reduced wall effect

    International Nuclear Information System (INIS)

    A proportional counter, using gaseous sources, in which the wall effects are considerably reduced, is described. The counter is fitted with a ring of internal shielding counters in anti-coincidence, separated from the main central counter only by a number of cathode wires. The counter can be readily assembled, giving flexibility in research investigations. Applications to a measurement of the L/K capture ratio in A37 and Fe55 are described. (author)

  5. 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.)

  6. 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...

  7. 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...

  8. 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...

  9. 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.

  10. 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...

  11. Do Hedge Funds Reduce Idiosyncratic Risk?

    OpenAIRE

    Namho Kang; Peter Kondor; Ronnie Sadka

    2012-01-01

    This paper studies the effect of hedge-fund trading on idiosyncratic risk. We hypothesize that while hedge-fund activity would often reduce idiosyncratic risk, high initial levels of idiosyncratic risk might be further amplified due to fund loss limits. Panel-regression analyses provide supporting evidence for this hypothesis. The results are robust to sample selection and are further corroborated by a natural experiment using the Lehman bankruptcy as an exogenous adverse shock to hedge-fund ...

  12. How Damage Diversification Can Reduce Systemic Risk

    OpenAIRE

    Burkholz, Rebekka; Garas, Antonios; Schweitzer, Frank

    2015-01-01

    We consider the problem of risk diversification in complex networks. Nodes represent e.g. financial actors, whereas weighted links represent e.g. financial obligations (credits/debts). Each node has a risk to fail because of losses resulting from defaulting neighbors, which may lead to large failure cascades. Classical risk diversification strategies usually neglect network effects and therefore suggest that risk can be reduced if possible losses (i.e., exposures) are split among many neighbo...

  13. 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...

  14. Reducing Product Diversity in Higher Education

    OpenAIRE

    Kelchtermans, Stijn; Verboven, Frank

    2009-01-01

    Public systems of higher education have recently attempted to cut costs by providing financial incentives to cut duplicated programs, i.e. programs that are offered at different institutions. We study the profit and welfare effects of reducing program duplication, against the background of a funding system reform in Flanders (Belgium). We find that dropping duplicated programs at individual institutions tends to be socially undesirable, due to the students' low willingness to travel to other ...

  15. 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.

  16. 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.

  17. Can Alcohol Prohibition Reduce Violence against Women?

    OpenAIRE

    Dara Lee Luca; Emily Owens; Gunjan Sharma

    2015-01-01

    Violence against women is a critical problem across the world. In this paper, we exploit state and temporal variation in alcohol control in India to examine the impact of prohibition on alcohol consumption and violent crimes against women. We first use detailed household survey data to show that prohibition policies are associated with substantially lower rates of drinking among men and domestic violence. Next, we provide evidence that alcohol prohibition reduces aggregate violence against wo...

  18. 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...

  19. Penerapan Reduced Impact Logging Menggunakan Monocable Winch (Pancang Tarik (Implementing Reduced Impact Logging with Monocable Winch

    Directory of Open Access Journals (Sweden)

    Yosep Ruslim

    2012-01-01

    Full Text Available Forest harvesting still encounters many problems especially concerning impact to the residual stand  and environmental damage. Implementing the reduced impact monocable winch and planning of good skid trails should have a positive impact on work efficiency as well as, reducing damage to the residual stand and soil during felling and skidding activities. Reduced impact logging (RIL with a monocable winch (Pancang Tarik system has been tried in several IUPHHKs and it can be concluded that RIL monocable winch system could be applied practically and reduce impact on residual stand and soil damage. Using this technology has many advantages, among others: cost efficiency, locally made, environmental friendly, and high local community participation. Application of  the monocable winch  system in reduced impact logging is an effort to reduce economical and environment  damages when compared to conventional system of ground based skidding with bulldozer system. The aim of this research is to verify the efficiency (operational cost, effectiveness (productivity and  time consumption of monocable winch system. The results  indicate that the implementation monocable winch system, has reduced the soil damage as much as 8% ha-1.  The skidding cost  with monocable system is Rp95.000 m-3. This figure is significantly cheaper if compare with ground base skidding with bulldozer system in which the skidding cost around Rp165.000 m-3.Keywords: mononocable winch, productivity,  skidding cost, reduced impact logging, local community

  20. Detecting reduced renal function in children

    DEFF Research Database (Denmark)

    Andersen, Trine Borup; Jødal, Lars; Erlandsen, Erland J;

    2013-01-01

    using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results.Methods Glomerular filtration rate was measured by plasma clearance of 51Cr-EDTA (13.7–147.4 mL/min/1.73 m2) in 119 children (age range 2.3–14.9 years).Reduced renal...... function was defined as a GFR of<82 mL/min/1.73 m2. SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone.......Results The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629–637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221–230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50–57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other...