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Sample records for chloroquine tolerance phenotype

  1. 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.

  2. 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...

  3. Phenotyping for Abiotic Stress Tolerance in Maize

    Institute of Scientific and Technical Information of China (English)

    Benhilda Masuka; Jose Luis Araus; Biswanath Das; Kai Sonder; Jill E. Cairns

    2012-01-01

    The ability to quickly develop germplasm having tolerance to several complex polygenic inherited abiotic and biotic stresses combined is critical to the resilience of cropping systems in the face of climate change.Molecular breeding offers the tools to accelerate cereal breeding; however,suitable phenotyping protocols are essential to ensure that the much-anticipated benefits of molecular breeding can be realized.To facilitate the full potential of molecular tools,greater emphasis needs to be given to reducing the within-experimental site variability,application of stress and characterization of the environment and appropriate phenotyping tools.Yield is a function of many processes throughout the plant cycle,and thus integrative traits that encompass crop performance over time or organization level (i.e.canopy level) will provide a better alternative to instantaneous measurements which provide only a snapshot of a given plant process.Many new phenotyping tools based on remote sensing are now available including non-destructive measurements of growth-related parameters based on spectral reflectance and infrared thermometry to estimate plant water status.Here we describe key field phenotyping protocols for maize with emphasis on tolerance to drought and low nitrogen.

  4. 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

  5. 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.)

  6. Field Phenotyping of Soybean Roots for Drought Stress Tolerance

    OpenAIRE

    Berhanu A. Fenta; Beebe, Stephen E.; Karl J. Kunert; James D. Burridge; Kathryn M. Barlow; Lynch, Jonathan P.; Foyer, Christine H.

    2014-01-01

    Root architecture was determined together with shoot parameters under well watered and drought conditions in the field in three soybean cultivars (A5409RG, Jackson and Prima 2000). Morphology parameters were used to classify the cultivars into different root phenotypes that could be important in conferring drought tolerance traits. A5409RG is a drought-sensitive cultivar with a shallow root phenotype and a root angle of <40°. In contrast, Jackson is a drought-escaping cultivar. It has a d...

  7. Chloroquine-induced pruritus

    Directory of Open Access Journals (Sweden)

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

    OpenAIRE

    Pearce, David A.; Carr, Carrie J.; Das, Biswadip; Sherman, Fred

    1999-01-01

    BTN1 of Saccharomyces cerevisiae encodes an ortholog of CLN3, the human Batten disease gene. We have reported previously that deletion of BTN1, btn1-Δ, resulted in a pH-dependent resistance to d-(−)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP). This phenotype was caused by btn1-Δ 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 ...

  9. 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...

  10. Chloroquine Phosphate Oral

    Science.gov (United States)

    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 ...

  11. PSYCHIATRIC COMPLICATIONS OF CHLOROQUINE

    OpenAIRE

    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...

  12. Biomarkers of tolerance: searching for the hidden phenotype.

    Science.gov (United States)

    Perucha, Esperanza; Rebollo-Mesa, Irene; Sagoo, Pervinder; Hernandez-Fuentes, Maria P

    2011-08-01

    Induction of transplantation tolerance remains the ideal long-term clinical and logistic solution to the current challenges facing the management of renal allograft recipients. In this review, we describe the recent studies and advances made in identifying biomarkers of renal transplant tolerance, from study inceptions, to the lessons learned and their implications for current and future studies with the same goal. With the age of biomarker discovery entering a new dimension of high-throughput technologies, here we also review the current approaches, developments, and pitfalls faced in the subsequent statistical analysis required to identify valid biomarker candidates. PMID:25018902

  13. Chloroquine Is a Zinc Ionophore

    OpenAIRE

    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...

  14. Chlorophyll a fluorescence to phenotype wheat genotypes for heat tolerance

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari; Andersen, Sven Bode; Ottosen, Carl-Otto;

    . Chlorophyll a fluorescence has been a versatile tool in photosynthesis research to measure plant responses to various abiotic stresses that affect PSII. We aim to establish a reproducible protocol to measure response of wheat genotypes to high temperature, based on the physiological marker, maximum quantum......%. Our protocol seems to be stable over environments since interaction between genotypes and the three repeated experiments separated in time was not statistically significant. The chlorophyll a fluorescence protocol may enable identification of wheat lines reliably more or less tolerant to heat stress...

  15. 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.

  16. Image-based phenotyping for non-destructive screening of different salinity tolerance traits in rice

    KAUST Repository

    Hairmansis, Aris

    2014-08-14

    Background Soil salinity is an abiotic stress wide spread in rice producing areas, limiting both plant growth and yield. The development of salt-tolerant rice requires efficient and high-throughput screening techniques to identify promising lines for salt affected areas. Advances made in image-based phenotyping techniques provide an opportunity to use non-destructive imaging to screen for salinity tolerance traits in a wide range of germplasm in a reliable, quantitative and efficient way. However, the application of image-based phenotyping in the development of salt-tolerant rice remains limited. Results A non-destructive image-based phenotyping protocol to assess salinity tolerance traits of two rice cultivars (IR64 and Fatmawati) has been established in this study. The response of rice to different levels of salt stress was quantified over time based on total shoot area and senescent shoot area, calculated from visible red-green-blue (RGB) and fluorescence images. The response of rice to salt stress (50, 75 and 100 mM NaCl) could be clearly distinguished from the control as indicated by the reduced increase of shoot area. The salt concentrations used had only a small effect on the growth of rice during the initial phase of stress, the shoot Na+ accumulation independent phase termed the ‘osmotic stress’ phase. However, after 20 d of treatment, the shoot area of salt stressed plants was reduced compared with non-stressed plants. This was accompanied by a significant increase in the concentration of Na+ in the shoot. Variation in the senescent area of the cultivars IR64 and Fatmawati in response to a high concentration of Na+ in the shoot indicates variation in tissue tolerance mechanisms between the cultivars. Conclusions Image analysis has the potential to be used for high-throughput screening procedures in the development of salt-tolerant rice. The ability of image analysis to discriminate between the different aspects of salt stress (shoot ion

  17. Eradication and phenotypic tolerance of Burkholderia cenocepacia biofilms exposed to atmospheric pressure non-thermal plasma.

    Science.gov (United States)

    Alshraiedeh, Nida H; Higginbotham, Sarah; Flynn, Padrig B; Alkawareek, Mahmoud Y; Tunney, Michael M; Gorman, Sean P; Graham, William G; Gilmore, Brendan F

    2016-06-01

    Chronic lung infection with bacteria from the Burkholderia cepacia complex (BCC), and in particular B. cenocepacia, is associated with significant morbidity and mortality in patients with cystic fibrosis (CF). B. cenocepacia can spread from person to person and exhibits intrinsic broad-spectrum antibiotic resistance. Recently, atmospheric pressure non-thermal plasmas (APNTPs) have gained increasing attention as a novel approach to the prevention and treatment of a variety of hospital-acquired infections. In this study, we evaluated an in-house-designed kHz-driven plasma source for the treatment of biofilms of a number of clinical CF B. cenocepacia isolates. The results demonstrated that APNTP is an effective and efficient tool for the eradication of B. cenocepacia biofilms but that efficacy is highly variable across different isolates. Determination of phenotypic differences between isolates in an attempt to understand variability in plasma tolerance revealed that isolates which are highly tolerant to APNTP typically produce biofilms of greater biomass than their more sensitive counterparts. This indicates a potential role for biofilm matrix components in biofilm tolerance to APNTP exposure. Furthermore, significant isolate-dependent differences in catalase activity in planktonic bacteria positively correlated with phenotypic resistance to APNTP by isolates grown in biofilms. PMID:27179816

  18. A three-tier phenotyping approach for hunting QTLs related to heat tolerance in bread wheat

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari; Rosenqvist, Eva; Ottosen, Carl-Otto;

    functionality, therefore, its physiological relevance in terms of overall plant performance was validated under moderate heat stress (36°C for a week) mimicking natural heat waves. Interestingly, the wheat cultivars previously selected for high Fv/Fm also showed higher net photosynthesis,chlorophyll content......, stomatal conductance and transpiration rate, suggesting that the tolerant cultivars had better evaporative cooling and stay green characteristics under heat stress. Further, cultivar Fv/Fm and dry matter content also showed a significant positive correlation. Tier 3: Linking phenotypic differences to QTLs...

  19. High-throughput phenotyping to detect drought tolerance QTL in wild barley introgression lines.

    Directory of Open Access Journals (Sweden)

    Nora Honsdorf

    Full Text Available Drought is one of the most severe stresses, endangering crop yields worldwide. In order to select drought tolerant genotypes, access to exotic germplasm and efficient phenotyping protocols are needed. In this study the high-throughput phenotyping platform "The Plant Accelerator", Adelaide, Australia, was used to screen a set of 47 juvenile (six week old wild barley introgression lines (S42ILs for drought stress responses. The kinetics of growth development was evaluated under early drought stress and well watered treatments. High correlation (r=0.98 between image based biomass estimates and actual biomass was demonstrated, and the suitability of the system to accurately and non-destructively estimate biomass was validated. Subsequently, quantitative trait loci (QTL were located, which contributed to the genetic control of growth under drought stress. In total, 44 QTL for eleven out of 14 investigated traits were mapped, which for example controlled growth rate and water use efficiency. The correspondence of those QTL with QTL previously identified in field trials is shown. For instance, six out of eight QTL controlling plant height were also found in previous field and glasshouse studies with the same introgression lines. This indicates that phenotyping juvenile plants may assist in predicting adult plant performance. In addition, favorable wild barley alleles for growth and biomass parameters were detected, for instance, a QTL that increased biomass by approximately 36%. In particular, introgression line S42IL-121 revealed improved growth under drought stress compared to the control Scarlett. The introgression line showed a similar behavior in previous field experiments, indicating that S42IL-121 may be an attractive donor for breeding of drought tolerant barley cultivars.

  20. High-throughput phenotyping to detect drought tolerance QTL in wild barley introgression lines

    KAUST Repository

    Honsdorf, Nora

    2014-05-13

    Drought is one of the most severe stresses, endangering crop yields worldwide. In order to select drought tolerant genotypes, access to exotic germplasm and efficient phenotyping protocols are needed. In this study the high-throughput phenotyping platform "The Plant Accelerator", Adelaide, Australia, was used to screen a set of 47 juvenile (six week old) wild barley introgression lines (S42ILs) for drought stress responses. The kinetics of growth development was evaluated under early drought stress and well watered treatments. High correlation (r = 0.98) between image based biomass estimates and actual biomass was demonstrated, and the suitability of the system to accurately and non-destructively estimate biomass was validated. Subsequently, quantitative trait loci (QTL) were located, which contributed to the genetic control of growth under drought stress. In total, 44 QTL for eleven out of 14 investigated traits were mapped, which for example controlled growth rate and water use efficiency. The correspondence of those QTL with QTL previously identified in field trials is shown. For instance, six out of eight QTL controlling plant height were also found in previous field and glasshouse studies with the same introgression lines. This indicates that phenotyping juvenile plants may assist in predicting adult plant performance. In addition, favorable wild barley alleles for growth and biomass parameters were detected, for instance, a QTL that increased biomass by approximately 36%. In particular, introgression line S42IL-121 revealed improved growth under drought stress compared to the control Scarlett. The introgression line showed a similar behavior in previous field experiments, indicating that S42IL-121 may be an attractive donor for breeding of drought tolerant barley cultivars. © 2014 Honsdorf et al.

  1. Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.

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    Patrick Kaiser

    2014-02-01

    Full Text Available In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN, the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.

  2. Screening of Bread Wheat Genotypes for Drought Tolerance Using Phenotypic and Proline Analyses.

    Science.gov (United States)

    Mwadzingeni, Learnmore; Shimelis, Hussein; Tesfay, Samson; Tsilo, Toi J

    2016-01-01

    Drought stress is one of the leading constraints to wheat (Triticum aestivum L.) production globally. Breeding for drought tolerance using novel genetic resources is an important mitigation strategy. This study aimed to determine the level of drought tolerance among diverse bread wheat genotypes using agronomic traits and proline analyses and to establish correlation of proline content and agronomic traits under drought-stress conditions in order to select promising wheat lines for breeding. Ninety-six diverse genotypes including 88 lines from the International Maize and Wheat Improvement Center (CIMMYT)'s heat and drought nurseries, and eight local checks were evaluated under greenhouse and field conditions during 2014/15 and 2015/16 making four testing environments. The following phenotypic traits were collected after stress imposed during the heading to anthesis period: the number of days to heading (DTH), days to maturity (DTM), productive tiller number (TN), plant height (PH), spike length (SL), spikelet per spike (SPS), kernels per spike (KPS), thousand kernel weight (TKW) and grain yield (GY) and proline content (PC). Analysis of variance, Pearson's correlation coefficient, principal component and stress tolerance index were calculated. Genotypes with high yield performance under stressed and optimum conditions maintained high values for yield components. Proline content significantly increased under stress, but weakly correlated with agronomic traits under both optimal and water limited conditions. The positive correlation observed between grain yield and proline content under-drought stress conditions provides evidence that proline accumulation might ultimately be considered as a tool for effective selection of drought tolerant genotypes. The study selected 12 genotypes with high grain yields under drought stressed conditions and favorable adaptive traits useful for breeding. PMID:27610116

  3. Thermal Tolerance in Widespread and Tropical Drosophila Species: Does Phenotypic Plasticity Increase with Latitude?

    DEFF Research Database (Denmark)

    Overgaard, Johannes; Kristensen, Torsten Nygård; Mitchell, Katherin A;

    2011-01-01

    The distribution of insects can often be related to variation in their response to thermal extremes, which in turn may reflect differences in plastic responses or innate variation in resistance. Species with widespread distributions are expected to have evolved higher levels of plasticity than....... The results do not support the hypothesis that widely distributed species have larger phenotypic plasticity for thermal tolerance limits, and Drosophila species distributions are therefore more closely linked to differences in innate thermal tolerance limits....

  4. Effect of chloroquine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    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...

  5. 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...

  6. Neuropilin-1 expression is induced on tolerant self-reactive CD8+ T cells but is dispensable for the tolerant phenotype.

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    Stephanie R Jackson

    Full Text Available Establishing peripheral CD8(+ T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment to tumor immunity since tumors are derived from self-tissue and often induce T cell tolerance and dysfunction. Thus, understanding the mechanisms that regulate T cell tolerance versus immunity has important implications for human health. Signals received from the tissue environment largely dictate whether responding T cells become activated or tolerant. For example, induced expression and subsequent ligation of negative regulatory receptors on the surface of self-reactive CD8(+ T cells are integral in the induction of tolerance. We utilized a murine model of T cell tolerance to more completely define the molecules involved in this process. We discovered that, in addition to other known regulatory receptors, tolerant self-reactive CD8(+ T cells distinctly expressed the surface receptor neuropilin-1 (Nrp1. Nrp1 was highly induced in response to self-antigen, but only modestly when the same antigen was encountered under immune conditions, suggesting a possible mechanistic link to T cell tolerance. We also observed a similar Nrp1 expression profile on human tumor infiltrating CD4(+ and CD8(+ T cells. Despite high expression on tolerant CD8(+ T cells, our studies revealed that Nrp1 had no detectable role in the tolerant phenotype. Specifically, Nrp1-deficient T cells displayed the same functional defects as wild-type self-reactive T cells, lacking in vivo cytolytic potential, IFNγ production, and antitumor responses. While reporting mostly negative data, our findings have therapeutic implications, as Nrp1 is now being targeted for human cancer therapy in clinical trials, but the precise molecular pathways and immune cells being engaged during treatment remain incompletely defined.

  7. 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.

  8. Fast forward genetics to identify mutations causing a high light tolerant phenotype in Chlamydomonas reinhardtii by whole-genome-sequencing

    OpenAIRE

    Schierenbeck, Lisa; Ries, David; Rogge, Kristin; Grewe, Sabrina; Weisshaar, Bernd; Kruse, Olaf

    2015-01-01

    Background: High light tolerance of microalgae is a desired phenotype for efficient cultivation in large scale production systems under fluctuating outdoor conditions. Outdoor cultivation requires the use of either wild-type or non-GMO derived mutant strains due to safety concerns. The identification and molecular characterization of such mutants derived from untagged forward genetics approaches was limited previously by the tedious and time-consuming methods involving techniques such as ...

  9. Association analysis of frost tolerance in rye using candidate genes and phenotypic data from controlled, semi-controlled, and field phenotyping platforms

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    Li Yongle

    2011-10-01

    Full Text Available Abstract Background Frost is an important abiotic stress that limits cereal production in the temperate zone. As the most frost tolerant small grain cereal, rye (Secale cereale L. is an ideal cereal model for investigating the genetic basis of frost tolerance (FT, a complex trait with polygenic inheritance. Using 201 genotypes from five Eastern and Middle European winter rye populations, this study reports a multi-platform candidate gene-based association analysis in rye using 161 single nucleotide polymorphisms (SNPs and nine insertion-deletion (Indel polymorphisms previously identified from twelve candidate genes with a putative role in the frost responsive network. Results Phenotypic data analyses of FT in three different phenotyping platforms, controlled, semi-controlled and field, revealed significant genetic variations in the plant material under study. Statistically significant (P ScCbf15 and one in ScCbf12, all leading to amino acid exchanges, were significantly associated with FT over all three phenotyping platforms. Distribution of SNP effect sizes expressed as percentage of the genetic variance explained by individual SNPs was highly skewed towards zero with a few SNPs obtaining large effects. Two-way epistasis was found between 14 pairs of candidate genes. Relatively low to medium empirical correlations of SNP-FT associations were observed across the three platforms underlining the need for multi-level experimentation for dissecting complex associations between genotypes and FT in rye. Conclusions Candidate gene based-association studies are a powerful tool for investigating the genetic basis of FT in rye. Results of this study support the findings of bi-parental linkage mapping and expression studies that the Cbf gene family plays an essential role in FT.

  10. Conserved synteny at the protein family level reveals genes underlying Shewanella species cold tolerance and predicts their novel phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Karpinets, Tatiana V.; Obraztsova, Anna; Wang, Yanbing; Schmoyer, Denise D.; Kora, Guruprasad; Park, Byung H.; Serres, Margrethe H.; Romine, Margaret F.; Land, Miriam L.; Kothe, Terence B.; Fredrickson, Jim K.; Nealson, Kenneth H.; Uberbacher, Edward

    2010-03-01

    Bacteria of the genus Shewanella can thrive in different environments and demonstrate significant variability in their metabolic and ecophysiological capabilities including cold and salt tolerance. Genomic characteristics underlying this variability across species are largely unknown. In this study we address the problem by a comparison of the physiological, metabolic and genomic characteristics of 19 sequenced Shewanella species. We have employed two novel approaches based on association of a phenotypic trait with the number of the trait-specific protein families (Pfam domains) and on the conservation of synteny (order in the genome) of the trait-related genes. Our first approach is top-down and involves experimental evaluation and quantification of the species’ cold tolerance followed by identification of the correlated Pfam domains and genes with a conserved synteny. The second, a bottom-up approach, predicts novel phenotypes of the species by calculating profiles of each Pfam domain among their genomes and following pair-wise correlation of the profiles and their network clustering. Using the first approach we find a link between cold and salt tolerance of the species and the presence in the genome of a Na+/H+ antiporter gene cluster. Other cold tolerance related genes includes peptidases, chemotaxis sensory transducer proteins, a cysteine exporter, and helicases. Using the bottom-up approach we found several novel phenotypes in the newly sequenced Shewanella species, including degradation of aromatic compounds by an aerobic hybrid pathway in S. woodyi, degradation of ethanolamine by S. benthica, and propanediol degradation by S. putrefaciens CN32 and S. sp. W3-18-1.

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

    Science.gov (United States)

    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

  12. Determination of chloroquine and monodesethylchloroquine in hair.

    Science.gov (United States)

    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

  13. Chloroquine use improves dengue-related symptoms

    Directory of Open Access Journals (Sweden)

    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.

  14. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech....

  15. Phenotyping of wheat cultivars for heat tolerance using chlorophyll a fluorescence

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari; Andersen, Svend Bode; Ottosen, Carl-Otto; Rosenqvist, Eva

    2012-01-01

    Abstract. In view of the global climate change, heat stress is an increasing constraint for the productivity of wheat (Triticum aestivum L.). Our aim was to identify contrasting cultivars in terms of heat tolerance by mass screening of 1274 wheat cultivars of diverse origin, based on a...... a milder heat stress of 38Cin 300 mmolm–2 s–1 for 2 h with preheating at 33–35Cfor 19 h in 7–14 mmolm–2 s–1 light showed a genetic determination of 8.52.7%.Aheat treatment of 40Cin 300 mmolm–2 s–1 for 72 h in the second screening with 138 selected cultivars resulted in larger differentiation of...... cultivars with an increased genetic component (15.43.6%), which was further increased to 27.96.8% in the third screening with 41 contrasting cultivars. This contrasting set of cultivars was then used to compare the ability of chlorophyll fluorescence parameters to detect genetic difference in heat tolerance...

  16. 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

  17. Thrombospondin-1-N-Terminal Domain Induces a Phagocytic State and Thrombospondin-1-C-Terminal Domain Induces a Tolerizing Phenotype in Dendritic Cells

    Science.gov (United States)

    Tabib, Adi; Krispin, Alon; Trahtemberg, Uriel; Verbovetski, Inna; Lebendiker, Mario; Danieli, Tsafi; Mevorach, Dror

    2009-01-01

    In our previous study, we have found that thrombospondin-1 (TSP-1) is synthesized de novo upon monocyte and neutrophil apoptosis, leading to a phagocytic and tolerizing phenotype of dendritic cells (DC), even prior to DC-apoptotic cell interaction. Interestingly, we were able to show that heparin binding domain (HBD), the N-terminal portion of TSP-1, was cleaved and secreted simultaneously in a caspase- and serine protease- dependent manner. In the current study we were interested to examine the role of HBD in the clearance of apoptotic cells, and whether the phagocytic and tolerizing state of DCs is mediated by the HBD itself, or whether the entire TSP-1 is needed. Therefore, we have cloned the human HBD, and compared its interactions with DC to those with TSP-1. Here we show that rHBD by itself is not directly responsible for immune paralysis and tolerizing phenotype of DCs, at least in the monomeric form, but has a significant role in rendering DCs phagocytic. Binding of TSP-1-C-terminal domain on the other hand induces a tolerizing phenotype in dendritic cells. PMID:19721725

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Thrombospondin-1-N-Terminal Domain Induces a Phagocytic State and Thrombospondin-1-C-Terminal Domain Induces a Tolerizing Phenotype in Dendritic Cells

    OpenAIRE

    Tabib, Adi; Krispin, Alon; Trahtemberg, Uriel; Verbovetski, Inna; Lebendiker, Mario; Danieli, Tsafi; Mevorach, Dror

    2009-01-01

    In our previous study, we have found that thrombospondin-1 (TSP-1) is synthesized de novo upon monocyte and neutrophil apoptosis, leading to a phagocytic and tolerizing phenotype of dendritic cells (DC), even prior to DC-apoptotic cell interaction. Interestingly, we were able to show that heparin binding domain (HBD), the N-terminal portion of TSP-1, was cleaved and secreted simultaneously in a caspase- and serine protease- dependent manner. In the current study we were interested to examine ...

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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...

  2. 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...

  3. Phenotypic and genetic characteristics associated with Listeria monocytogenes food chain isolates displaying enhanced and diminished cold tolerance

    DEFF Research Database (Denmark)

    Hingston, P.; Chen, J.; Laing, C.;

    The potentially fatal human pathogen Listeria monocytogenes (Lm) is most recognizedfor its ability to contaminate foods and grow during refrigerated storage. Given the importance of preventing Lm from reaching dangerous levels in food, little is known about the genetic and physiological differences...... in brainheart infusion broth, for their ability to tolerate cold (4°C), salt (6% NaCl, 25°C), acid (pH 5, 25°C), and desiccation (33% RH, 20°C) stress. Isolates were considered tolerant or sensitive if they exhibited survival characteristics > or < than the mean±1SD. Remaining isolates were.......012) lag phases in salt than cold sensitive isolates, and a positive correlation (p=0.002, r=0.239) existed between growth rates of isolates under salt and acid stress. A whole genome single-nucleotide-variants (SNVs) phylogeny revealed closely related cold tolerant and sensitive isolates, suggesting that...

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

    International Nuclear Information System (INIS)

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

  5. 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 ...

  6. Biocide tolerance, phenotypic and molecular response of lactic acid bacteria isolated from naturally-fermented Aloreña table to different physico-chemical stresses.

    Science.gov (United States)

    Casado Muñoz, María Del Carmen; Benomar, Nabil; Lavilla Lerma, Leyre; Knapp, Charles W; Gálvez, Antonio; Abriouel, Hikmate

    2016-12-01

    Lactic acid bacteria (LAB) isolated throughout the fermentation process of Aloreña table olives were found to be resistant at least to three antibiotics (Casado Muñoz et al., 2014); however, most were sensitive to the biocides tested in this study (with minimum inhibitory concentrations [MIC] below the epidemiological cut-off values). 2-15% of the isolates were found to be biocide resistant: Leuconostoc Pseudomesenteroides, which were resistant to hexachlorophene, and Lactobacillus pentosus to cetrimide and hexadecylpiridinium. We analyzed the effect of different physico-chemical stresses, including antimicrobials, on the phenotypic and genotypic responses of LAB, providing new insights on how they become resistant in a changing environment. Results indicated that similar phenotypic responses were obtained under three stress conditions: antimicrobials, chemicals and UV light. Susceptibility patterns to antibiotics changed: increasing MICs for ampicillin, chloramphenicol, ciprofloxacin, teicoplanin and tetracycline, and decreasing the MICs for clindamycin, erythromycin, streptomycin and trimethoprim in most strains. Statistically, cross resistance between different antibiotics was detected in all stress conditions. However, expression profiles of selected genes involved in stress/resistance response (rpsL, recA, uvrB and srtA) differed depending on the stress parameter, LAB species and strain, and the target gene. We conclude that, despite the uniform phenotypic response to stresses, the repertoire of induced and repressed genes differs. So, a search for a target to improve stress tolerance of LAB, especially those of importance as starter/protective cultures or probiotics, may depend on the individual screening of each strain, even though we could predict the antibiotic phenotypic response to all stresses. PMID:27554140

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

    Directory of Open Access Journals (Sweden)

    Bray Patrick G

    2011-02-01

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

  8. 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

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

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

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

  10. 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...

  11. 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.

  12. 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...

  13. 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.

  14. 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...

  15. Responses of sensitive and tolerant bush beans (Phaseolus vulgaris L.) to ozone in open-top chambers are influenced by phenotypic differences, morphological characteristics, and the chamber environment

    Energy Technology Data Exchange (ETDEWEB)

    Elagoez, Vahram [Plant Biology Graduate Program, University of Massachusetts, Amherst, MA 01003 (United States)]. E-mail: velagoz@nsm.umass.edu; Manning, William J. [Department of Plant, Soil and Insect Sciences, University of Massachusetts, Amherst, MA 01003 (United States)

    2005-08-15

    Responses of bush bean (Phaseolus vulgaris L.) lines 'S156' (O{sub 3}-sensitive) and 'R123' (O{sub 3}-tolerant), and cultivars 'BBL 290' (O{sub 3}-sensitive) and 'BBL 274' (O{sub 3}-tolerant) to ambient ozone (O{sub 3}) were investigated during the 2001 and 2002 growing seasons. Seedlings were grown in pots inside open-top chambers (OTCs), with charcoal filtered (CF) and non-filtered (NF) ambient air, and in non-chambered ambient air (AA) plots. Growth parameters from individual plants were evaluated after harvests at the end of vegetative (V{sub 4}) and reproductive (R{sub 10}) growth phases. Results at V{sub 4} indicated that CF did not provide additional benefits over NF in 'S156' in 2001 and 2002. In contrast, exposure to CF significantly impaired the growth of 'R123'. At the end of R{sub 10}, 'S156' produced more pods, most of which remained immature, and contained fewer seeds or were more frequently aborted, whereas pods produced in 'R123' reached pod maturation and senescence more consistently. Despite increased seed weights inside the OTCs, as observed in 'S156', differences between the two lines were insignificant when grown outside OTCs. Results from the 'BBL 290'/'BBL 274' pair, especially at V{sub 4} phase, remained inconclusive. Plant morphological characteristics, variabilities in environmental conditions, and 'chamber effects' inside OTCs were influential in determining plant response to ambient O{sub 3}. - Phenotypic differences, morphological characteristics, and 'chamber effects' inside OTCs are equally influential in determining the responses of beans to O{sub 3}.

  16. 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.

  17. 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)

  18. 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...

  19. Functional and phenotypic characterization of a protein from Lactobacillus acidophilus involved in cell morphology, stress tolerance and adherence to intestinal cells.

    Science.gov (United States)

    O'Flaherty, Sarah J; Klaenhammer, Todd R

    2010-11-01

    Structural components of the cell surface have an impact on some of the beneficial attributes of probiotic bacteria. In silico analysis of the L. acidophilus NCFM genome sequence revealed the presence of a putative cell surface protein that was predicted to be a myosin cross-reactive antigen (MCRA). As MCRAs are conserved among many probiotic bacteria, we used the upp-based counterselective gene replacement system, designed recently for use in L. acidophilus, to determine the functional role of this gene (LBA649) in L. acidophilus NCFM. Phenotypic assays were undertaken with the parent strain (NCK1909) and deletion mutant (NCK2015) to assign a function for this gene. The growth of NCK2015 (ΔLBA649) was reduced in the presence of lactate, acetate, porcine bile and salt. Adhesion of NCK2015 to Caco-2 cells was substantially reduced for both stationary-phase (∼45 % reduction) and exponential-phase cells (∼50 % reduction). Analysis of NCK2015 by scanning electron microscopy revealed a longer cell morphology after growth in MRS broth compared to NCK1909. These results indicate a role for LBA649 in stress tolerance, cell wall division and adherence to Caco-2 cells. PMID:20829293

  20. 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...

  1. 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....

  2. 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.

  3. 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

  4. Pleiotropic phenotypes of the salt-tolerant and cytosine hypomethylated leafless inflorescence, evergreen dwarf and irregular leaf lamina mutants of Catharanthus roseus possessing Mendelian inheritance

    Indian Academy of Sciences (India)

    Renu Kumari; Vishakha Sharma; Vinay Sharma; Sushil Kumar

    2013-12-01

    In Catharanthus roseus, three morphological cum salt-tolerant chemically induced mutants ofMendelian inheritance and their wild-type parent cv Nirmal were characterized for overall cytosine methylation at DNA repeats, expression of 119 protein-coding and seven miRNA-coding genes and 50 quantitative traits. The mutants, named after their principal morphological feature(s), were leafless inflorescence (lli), evergreen dwarf (egd) and irregular leaf lamina (ill). The Southern-blot analysis of MspI digested DNAs of mutants probed with centromeric and 5S and 18S rDNA probes indicated that, in comparison to wild type, the mutants were extensively demethylated at cytosine sites. Among the 126 genes investigated for transcriptional expression, 85 were upregulated and 41 were downregulated in mutants. All of the five genes known to be stress responsive had increased expression in mutants. Several miRNA genes showed either increased or decreased expression in mutants. The C. roseus counterparts of CMT3, DRM2 and RDR2 were downregulated in mutants. Among the cell, organ and plant size, photosynthesis and metabolism related traits studied, 28 traits were similarly affected in mutants as compared to wild type. Each of the mutants also expressed some traits distinctively. The egd mutant possessed superior photosynthesis and water retention abilities. Biomass was hyperaccumulated in roots, stems, leaves and seeds of the lli mutant. The ill mutant was richest in the pharmaceutical alkaloids catharanthine, vindoline, vincristine and vinblastine. The nature of mutations, origins of mutant phenotypes and evolutionary importance of these mutants are discussed.

  5. Pleiotropic phenotypes of the salt-tolerant and cytosine hypomethylated leafless inflorescence, evergreen dwarf and irregular leaf lamina mutants of Catharanthus roseus possessing Mendelian inheritance.

    Science.gov (United States)

    Kumari, Renu; Sharma, Vishakha; Sharma, Vinay; Kumar, Sushil

    2013-12-01

    In Catharanthus roseus, three morphological cum salt-tolerant chemically induced mutants of Mendelian inheritance and their wild-type parent cv Nirmal were characterized for overall cytosine methylation at DNA repeats, expression of 119 protein coding and seven miRNA-coding genes and 50 quantitative traits. The mutants, named after their principal morphological feature(s), were leafless inflorescence (lli), evergreen dwarf (egd) and irregular leaf lamina (ill). The Southern-blot analysis of MspI digested DNAs of mutants probed with centromeric and 5S and 18S rDNA probes indicated that, in comparison to wild type, the mutants were extensively demethylated at cytosine sites. Among the 126 genes investigated for transcriptional expression, 85 were upregulated and 41 were downregulated in mutants. All of the five genes known to be stress responsive had increased expression in mutants. Several miRNA genes showed either increased or decreased expression in mutants. The C. roseus counterparts of CMT3, DRM2 and RDR2 were downregulated in mutants. Among the cell, organ and plant size, photosynthesis and metabolism related traits studied, 28 traits were similarly affected in mutants as compared to wild type. Each of the mutants also expressed some traits distinctively. The egd mutant possessed superior photosynthesis and water retention abilities. Biomass was hyperaccumulated in roots, stems, leaves and seeds of the lli mutant. The ill mutant was richest in the pharmaceutical alkaloids catharanthine, vindoline, vincristine and vinblastine. The nature of mutations, origins of mutant phenotypes and evolutionary importance of these mutants are discussed. PMID:24371160

  6. Evaluation of Sensitivity of Plasmodium vivax to Chloroquine

    Directory of Open Access Journals (Sweden)

    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.

  7. 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...

  8. 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...

  9. 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 ...

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

    OpenAIRE

    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...

  11. 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...

  12. 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 ...

  13. 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.

  14. Acrolein Exposure Blocks Down-Regulation of Cytokines and IgE Antibody in a Mucosal Tolerance Model but does not Alter Phenotypic Markers of Allergic Lung Disease

    Science.gov (United States)

    Acrolein (ACR) is a highly reactive upper airway toxicant that humans are exposed in a variety of environmental situations. Here we examined the effect of ACR exposure on development of immune tolerance in mice. To induce tolerance, female BALB/C mice were intranasally inoculate...

  15. 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

  16. 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.

  17. 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

  18. 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...

  19. 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 ...

  20. 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...

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. Color vision loss in patients treated with chloroquine

    Directory of Open Access Journals (Sweden)

    Ventura Dora F.

    2003-01-01

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

  6. Gsα Deficiency in Adipose Tissue Leads to a Lean Phenotype with Divergent Effects on Cold Tolerance and Diet-Induced Thermogenesis

    OpenAIRE

    Chen, Min; Chen, Hui; Nguyen, Annie; Gupta, Divakar; Jie WANG; Lai, Edwin W.; Pacak, Karel; Gavrilova, Oksana; Michael J Quon; Weinstein, Lee S.

    2010-01-01

    Gsα, the G protein which mediates receptor-stimulated cAMP generation, has been implicated as a regulator of adipogenesis and adipose tissue function. Heterozygous Gsα mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients and in mice. In this study we generated mice with adipose-specific Gsα deficiency. Heterozygotes had 50% loss of Gsα expression in adipose tissue and no obvious phenotype, suggesting that adipose-specific Gsα deficiency is not the cause of obesity in...

  7. 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....

  8. 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...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. 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.

  11. 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

  12. 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

  13. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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.

  16. 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...

  17. 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...

  18. 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

  19. 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

  20. Relationships between phenotypic variation in osmotic adjustment, water-use efficiency, and drought tolerance of seven cultivars of Lotus corniculatus L.

    Directory of Open Access Journals (Sweden)

    Luis Inostroza

    2015-03-01

    Full Text Available Lotus corniculatus L. is a perennial forage legume species highly-adapted to growth under drought conditions. However, the genetic and physiological mechanisms involved in its adaptive capacity have not been elucidated. The role of osmotic adjustment (OA and water-use efficiency (WUE on the drought tolerance of L. corniculatus was studied in a greenhouse experiment. Seven cultivars of different origin were subjected to two contrasting treatments of available soil water: No water stress (NWS and with water stress (WWS. Xylem water potential (Ψx, osmotic potential (Ψπ, pressure potential (Ψp, relative water content (RWC, stomatal conductance (g s, shoot DM production, water transpiration (T, and WUE (shoot DM/T were measured. Water treatments significantly (P < 0.05 affected plant water status, which was reflected in reduced Ψx, RWC, g s, and transpiration rate in the WWS treatment compared with the NWS treatment. All cultivars showed a high capacity for OA under WWS treatment because Ψπ decreased by approximately 60% and Ψp increased by approximately 30%, compared with the NWS treatment. Cultivars with a higher solute accumulation (low Ψπ value had the lowest DM production under WWS treatment. In contrast, WUE varied greatly among cultivars and was positively associated (R² = 0.88; P < 0.01 with DM production under drought conditions.

  1. 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

  2. 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.

  3. 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

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

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    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Tolerating Zero Tolerance?

    Science.gov (United States)

    Moore, Brian N.

    2010-01-01

    The concept of zero tolerance dates back to the mid-1990s when New Jersey was creating laws to address nuisance crimes in communities. The main goal of these neighborhood crime policies was to have zero tolerance for petty crime such as graffiti or littering so as to keep more serious crimes from occurring. Next came the war on drugs. In federal…

  7. 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

  8. 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.

  9. Alterações fenotípicas em cultivares de alface selecionadas para calor Phenotypical alterations in lettuce genotypes selected for heat tolerance

    Directory of Open Access Journals (Sweden)

    José Henrique Conti

    2000-11-01

    unselected ones of the same groups were analyzed for morphological variations, to quantify possible adaptative modifications for the cultivation conditions in heat seasons. Cultivars of the groups "butterhead" (Regina, Glória, IAC 303, IAC 202, Sem Rival and Luciana, "leaf-lettuce" (Grand Rapids and Brisa, and "crisphead" (Great Lakes and Mesa 659 were compared in two summer seasons, in Piracicaba, Brazil, in randomized blocks design. In the first (November/1990 were analyzed the characteristics of stomata number, leaf thickness and amount of chlorophyl of the whole plants. In the second (September/1991, were analyzed the characteristics of number of leaves, and dry and fresh weight of the whole plants. Cultivars selected for heat tolerance in the "butterhead" group (Gloria and Regina, presented larger stomata number (respectively 9,487/cm² and 7,973/cm² and thicker leaves (respectively 556 mm e 439 mm and, also, they accumulated larger amount of dry matter (respectively 24.55 g and 25.50 g, Cultivars selected for heat of the group "leaf-lettuce" (Brisa, accumulated larger amount of green matter (446.77g and dry ones (22.40 g, in the same way that presented larger stomata number (7,279/cm². For the cultivars of the group "crisphead", significant difference was just observed for leaf thickness; cv. Mesa 659 presented thicker leaves (589 mm. Significant increases of vegetal biomass were verified in cultivars selected for heat in relation to the unselected ones. Cultivars that reached larger dry matter yield were Mesa 659 (28.74 g, Great Lakes (27.17 g and Regina. The results checked that the slow bolting selection indirectly produced adaptative variations in the lettuce plants.

  10. 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.

  11. 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

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

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    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.

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

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    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.

  14. 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...

  15. 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.

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    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.

  16. 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...

  17. 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....

  18. 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

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

    Science.gov (United States)

    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

  20. 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

  1. 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.

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

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    Shailaja B Khobragade

    2013-01-01

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

  3. 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 ...

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

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    Janni Papakrivos

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

  5. 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

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    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

  8. 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...

  9. 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

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

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    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.

  11. 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.

  12. 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

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    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

  13. 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...

  14. 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....

  15. 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...

  16. 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...

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

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    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.

  18. 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...

  19. Phenotyping bananas for drought resistance

    OpenAIRE

    IyyakuttyRavi

    2013-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with ‘B’ genome are more tolerant to abiotic stresses than those solely based on ‘A’ genome. In particular, bananas with ‘ABB’ genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite f...

  20. Phenotyping bananas for drought resistance

    OpenAIRE

    Ravi, Iyyakkutty; Uma, Subbaraya; Vaganan, Muthu Mayil; Mustaffa, Mohamed M.

    2013-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with “B” genome are more tolerant to abiotic stresses than those solely based on “A” genome. In particular, bananas with “ABB” genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite f...

  1. 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.

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

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    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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

  9. Chloroquine 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

  10. 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

  11. 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...

  12. 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

  13. 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...

  14. 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.

  15. 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....

  16. 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...

  17. 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...

  18. 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

  19. 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

  20. 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

  1. Phenotypic variation in metabolism and morphology correlating with animal swimming activity in the wild: relevance for the OCLTT (oxygen- and capacity-limitation of thermal tolerance), allocation and performance models

    OpenAIRE

    Baktoft, Henrik; Jacobsen, Lene; Skov, Christian; Koed, Anders; Jepsen, Niels; Berg, Søren; Boel, Mikkel; Aarestrup, Kim; Svendsen, Jon Christian

    2016-01-01

    Ongoing climate change is affecting animal physiology in many parts of the world. Using metabolism, the oxygen- and capacitylimitation of thermal tolerance (OCLTT) hypothesis provides a tool to predict the responses of ectothermic animals to variation in temperature, oxygen availability and pH in the aquatic environment. The hypothesis remains controversial, however, and has been questioned in several studies. A positive relationship between aerobic metabolic scope and animal activity would b...

  2. 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

  3. 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

  4. Phenotypic approaches to drought in cassava: review.

    Science.gov (United States)

    Okogbenin, Emmanuel; Setter, Tim L; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2013-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12-18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding. PMID

  5. Phenotypic Approaches to Drought in Cassava: Review

    Directory of Open Access Journals (Sweden)

    Emmanuel eOkogbenin

    2013-05-01

    Full Text Available Cassava is an important crop in Africa, Asia, Latin America and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12 - 18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance

  6. 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)

  7. 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

  8. 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

  9. 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.

  10. 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...

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

    Science.gov (United States)

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

    2016-01-01

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

  12. 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

  13. Neuropilin-1 in Transplantation Tolerance

    Directory of Open Access Journals (Sweden)

    Mauricio eCampos-Mora

    2013-11-01

    Full Text Available In the immune system, Neuropilin-1 (Nrp1 is a molecule that plays an important role in establishing the immunological synapse between dendritic cells (DCs and T cells. Recently, Nrp1 has been identified as a marker that seems to distinguish natural T regulatory (nTreg cells, generated in the thymus, from inducible T regulatory (iTreg cells raised in the periphery. Given the crucial role of both nTreg and iTreg cells in the generation and maintenance of immune tolerance, the ability to phenotypically identify each of these cell populations in vivo is needed to elucidate their biological properties. In turn, these properties have the potential to be developed for therapeutic use to promote immune tolerance. Here we describe the nature and functions of Nrp1, including its potential use as a therapeutic target in transplantation tolerance.

  14. Drought Tolerance in Modern and Wild Wheat

    OpenAIRE

    Hikmet Budak; Melda Kantar; Kuaybe Yucebilgili Kurtoglu

    2013-01-01

    The genus Triticum includes bread (Triticum aestivum) and durum wheat (Triticum durum) and constitutes a major source for human food consumption. Drought is currently the leading threat on world's food supply, limiting crop yield, and is complicated since drought tolerance is a quantitative trait with a complex phenotype affected by the plant's developmental stage. Drought tolerance is crucial to stabilize and increase food production since domestication has limited the genetic diversity of c...

  15. 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.

  16. 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...

  17. 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....

  18. Salt Tolerance

    OpenAIRE

    Xiong, Liming; Zhu, Jian-Kang

    2002-01-01

    Studying salt stress is an important means to the understanding of plant ion homeostasis and osmo-balance. Salt stress research also benefits agriculture because soil salinity significantly limits plant productivity on agricultural lands. Decades of physiological and molecular studies have generated a large body of literature regarding potential salt tolerance determinants. Recent advances in applying molecular genetic analysis and genomics tools in the model plant Arabidopsis thaliana are sh...

  19. Phenotypic variation in metabolism and morphology correlating with animal swimming activity in the wild: relevance for the OCLTT (oxygen- and capacity-limitation of thermal tolerance), allocation and performance models

    Science.gov (United States)

    Baktoft, Henrik; Jacobsen, Lene; Skov, Christian; Koed, Anders; Jepsen, Niels; Berg, Søren; Boel, Mikkel; Aarestrup, Kim; Svendsen, Jon C.

    2016-01-01

    Ongoing climate change is affecting animal physiology in many parts of the world. Using metabolism, the oxygen- and capacity-limitation of thermal tolerance (OCLTT) hypothesis provides a tool to predict the responses of ectothermic animals to variation in temperature, oxygen availability and pH in the aquatic environment. The hypothesis remains controversial, however, and has been questioned in several studies. A positive relationship between aerobic metabolic scope and animal activity would be consistent with the OCLTT but has rarely been tested. Moreover, the performance model and the allocation model predict positive and negative relationships, respectively, between standard metabolic rate and activity. Finally, animal activity could be affected by individual morphology because of covariation with cost of transport. Therefore, we hypothesized that individual variation in activity is correlated with variation in metabolism and morphology. To test this prediction, we captured 23 wild European perch (Perca fluviatilis) in a lake, tagged them with telemetry transmitters, measured standard and maximal metabolic rates, aerobic metabolic scope and fineness ratio and returned the fish to the lake to quantify individual in situ activity levels. Metabolic rates were measured using intermittent flow respirometry, whereas the activity assay involved high-resolution telemetry providing positions every 30 s over 12 days. We found no correlation between individual metabolic traits and activity, whereas individual fineness ratio correlated with activity. Independent of body length, and consistent with physics theory, slender fish maintained faster mean and maximal swimming speeds, but this variation did not result in a larger area (in square metres) explored per 24 h. Testing assumptions and predictions of recent conceptual models, our study indicates that individual metabolism is not a strong determinant of animal activity, in contrast to individual morphology, which is

  20. 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.

  1. 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...

  2. 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...

  3. 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.

  4. 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...

  5. 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 ...

  6. 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

  7. 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)

  8. Debates in allergy medicine: baked egg and milk do not accelerate tolerance to egg and milk.

    Science.gov (United States)

    Dang, Thanh D; Peters, Rachel L; Allen, Katrina J

    2016-01-01

    There is emerging evidence that children with egg and cow's milk allergy who can tolerate these allergens cooked in baked goods are more likely to develop tolerance. As a result a hypothesis has arisen that exposure to egg and milk in baked goods may hasten tolerance development; however, it is unclear whether children who develop tolerance do so because they have ingested low levels of egg or milk in baked products. An alternative explanation for the improved prognosis in those who can tolerate food allergens in the baked form is that tolerance to egg and milk in baked goods is simply an indicator of a phenotype that is less likely to be persistent. We discuss the role that the baked egg or milk allergy phenotype plays on predicting tolerance development and suggest that it is the phenotype of the disease rather than exposure to altered allergens that is the strongest predictor of tolerance development. PMID:26839629

  9. 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

  10. 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.

  11. 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

  12. 紫外诱变筛选耐氧性Chlamydomonas moewusii产氢藻株%Screening of Oxygen-Tolerance Phenotypes in Hydrogen-Producing Strains of Chlamydomonas moewusii with Ultraviolet Radiation

    Institute of Scientific and Technical Information of China (English)

    张彦婷; 范晓蕾; 李潇萍; 郭荣波

    2011-01-01

    In order to reduce the sensitivity of hydrogenases in green algae to 02, four mutants of Chlamydomonas moewusii trains with improved oxygen-tolerance and hydrogen-evolving activities, namely Mu-l, Mu-2, Mu-3 and Mu-4, were generated via ultraviolet mutagenesis and were screened following an exposure to metronidazole and applied oxygen. Then, the screened strains were characterized by the hydrogenases activity in vivo, the respiration activity and the photosystem Ⅱ activity of algal cells. The results show that the hydrogenase activities in vivo of the four mutants are respectively 1.69, 2. 86, 1.06 and 1.80 times that of the wild type, that the residual activities of the mutants after a treatment with 1% O2 ( volume fraction) increase respectively from the original ( 20. 00 ± 2. 47)% to (34. 40 ±.4. 88)%, (32. 50 +2. 85)%, (55.60 +3.30)% and (43. 10 +8. 73)%, and that, there are no obvious differences in photosynthesis and respiration during the growth of Mu-l, Mu-2 and the wild type.%为解决绿藻中氢化酶对O2极为敏感的问题,以具高产氢催化活性的绿藻Chlamydomonas moewusii野生株作为出发藻株,通过紫外辐射,结合甲硝唑及外加氧法进行耐氧性产氢突变株的诱变和筛选,得到4株耐氧性及产氢活性均显著提高的突变藻株Mu-1、Mu-2、Mu-3、Mu-4,并进行了相应的氢化酶体内活性、呼吸活性与光系统Ⅱ光化学活性分析.结果表明,4株突变藻株的氢化酶体内活性约为野生株氢化酶体内活性的1.69、2.86、1.06和1.80倍,突变株经1%(体积分数)O2处理后,残留活性分别从野生株的(20.00±2.47)%提高到(34.40±4.88)%、(32.50±2.85)%、(55.60±3.30)%和(43.10±8.73)%,而Mu-1和Mu-2两株藻在生长过程中的的光合作用与呼吸作用均未发现明显变化.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. 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

  1. 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

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

    Directory of Open Access Journals (Sweden)

    Moon Rajkumar Sukdeo

    2012-09-01

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

  3. 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.

  4. 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.

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

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    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.

  6. 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

  7. 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

  8. 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....

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Rungsihirunrat Kanchana

    2011-02-01

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

  11. 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

  12. Toleration, Groups, and Multiculturalism

    DEFF Research Database (Denmark)

    Lægaard, Sune

    The chapter considers how groups might be relevant as objects of policies of toleration and the different senses 'group' might have in relation to questions of toleration. The chapter argues that groups can be relevant to toleration in several different ways as objects of toleration. Toleration is...... routinely defined as involving an objection component, a power requirement and an acceptance component. The objection and acceptance components refer to reasons or dispositions of the subjects of toleration, e.g. public authorities deciding how to act in relation to groups. The power condition refers to the...... toleration allows receivers of toleration to enjoy. The chapter shows how groups may be objects of toleration in different ways in relation to each of these components or conditions of toleration. The sense of 'group' relevant to toleration may differ when the group is an object of power, i.e. when others...

  13. Chlorophyll a fluorescence to phenotype wheat genotypes for heat tolerance

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari; Andersen, Sven Bode; Ottosen, Carl-Otto;

    In prospects of global climate change, heat stress is a rising constraint for the productivity of wheat (Triticum aestivum L.). It is a heat-susceptible crop beyond 17-23oC temperature throughout its phenological stages, flowering phase being the most sensitive stage. Chlorophyll a fluorescence...

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. Genetic Approaches to Develop Salt Tolerant Germplasm

    KAUST Repository

    Tester, Mark A.

    2015-08-19

    Forty percent of the world\\'s food is produced under irrigation, and this is directly threatened by over-exploitation and changes in the global environment. One way to address this threat is to develop systems for increasing our ability to use lower quality water, in particular saline water. Low cost partial desalination of brackish water, use of saline water for cooling and increases in the salinity tolerance of crops can all contribute to the development of this new agricultural system. In this talk, the focus will be on the use of forward genetic approaches for discovery of genes related to salinity tolerance in barley and tomatoes. Rather than studying salinity tolerance as a trait in itself, we dissect salinity tolerance into a series of components that are hypothesised to contribute to overall salinity tolerance (following the paradigm of Munns & Tester, 2008). For example, one significant component of tolerance of most crop plants to moderate soil salinity is due to the ability to maintain low concentrations of Na+ in the leaves, and much analysis of this aspect has been done (e.g. Roy et al., 2013, 2014). A major site for the control of shoot Na+ accumulation is at the plasma membrane of the mature stele of the root. Alleles of HKT, a major gene underlying this transport process have been characterized and, in work led by Dr Rana Munns (CSIRO), have now been introgressed into commercial durum wheat and led to significantly increased yields in saline field conditions (Munns et al., 2012). The genotyping of mapping populations is now highly efficient. However, the ability to quantitatively phenotype these populations is now commonly limiting forward progress in plant science. The increasing power of digital imaging and computational technologies offers the opportunity to relieve this phenotyping bottleneck. The Plant Accelerator is a 4500m2 growth facility that provides non-destructive phenotyping of large populations of plants (http

  2. 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.

  3. 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...

  4. 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...

  5. 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

  6. Immunological approaches for tolerance induction in allergy.

    Science.gov (United States)

    Conrad, Melanie L; Renz, Harald; Blaser, Kurt

    2011-01-01

    Allergy is the consequence of an inappropriate inflammatory immune response generated against harmless environmental antigens. In allergic disorders such as asthma and rhinitis, the Th2 mediated phenotype is a result of loss of peripheral tolerance mechanisms. In cases such as these, approaches such as immunotherapy attempt to treat the underlying cause of allergic disease by restoring tolerance. Immunotherapy initiates many complex mechanisms within the immune system that result in initiation of innate immunity, activation of both cellular and humoral B cell immunity, as well as triggering T regulatory subsets which are major players in the establishment of peripheral tolerance. Though studies clearly demonstrate immunotherapy to be efficacious, research to improve this treatment is ongoing. Investigation of allergenicity versus immunogenicity, native versus modified allergens, and the use of adjuvant and modality of dosing are all current strategies for immunotherapy advancement that will be reviewed in this article. PMID:21598104

  7. 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....

  8. 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.

  9. Lactose tolerance tests

    Science.gov (United States)

    Hydrogen breath test for lactose tolerance ... Two common methods include: Lactose tolerance blood test Hydrogen breath test The hydrogen breath test is the preferred method. It measures the amount of hydrogen ...

  10. Mechanisms of immunological tolerance.

    Science.gov (United States)

    Waldmann, Herman

    2016-03-01

    There is increasing interest in establishing diagnostic markers of immunological tolerance applicable to efforts to minimize drug immunosuppression in transplantation and chronic immunological diseases. It is hoped that an understanding of the diverse mechanisms that can contribute to tolerance will guide efforts to establish diagnostic tolerance biomarkers. Not only would these be valuable for management of autoimmune diseases, transplants and allergies, but they might also guide efforts to override tolerance processes in cancer and vaccine development. Where tolerance is generated by deletion or inactivation of antigen reactive lymphocytes, it is unlikely that any long-term-valid blood biomarkers might be found. Where tolerance is mediated by active regulatory mechanisms, indicators that can be usefully measured may emerge, but these would likely show significant heterogeneity reflecting the diversity of active tolerance processes operating in different individuals. Given this, the most useful "kits" might be those "smart" enough to detect this diversity of tolerance players. PMID:26036868

  11. 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.

  12. 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.

  13. Software fault tolerance

    OpenAIRE

    Kazinov, Tofik Hasanaga; Mostafa, Jalilian Shahrukh

    2009-01-01

    Because of our present inability to produce errorfree software, software fault tolerance is and will contiune to be an important consideration in software system. The root cause of software design errors in the complexity of the systems. This paper surveys various software fault tolerance techniquest and methodologies. They are two gpoups: Single version and Multi version software fault tolerance techniques. It is expected that software fault tolerance research will benefit from this research...

  14. Software for tolerance design

    OpenAIRE

    Shilo, Galina; Kovalenko, Daria; Gaponenko, Mykola

    2012-01-01

    Software for tolerance assignment and element selection is presented in the paper. Methods of tolerance design apply mathematical models of tolerance regions in shapes of hyperparallelepiped and hyperellipsoid which makes possible to take into consideration distribution laws of element parameters. The methods allow carrying element selection and tolerance assignment taking into account external influences. Specification of software functional characteristics and input data presentation were s...

  15. Genetic dissection of acetic acid tolerance in Saccharomyces cerevisiae.

    Science.gov (United States)

    Geng, Peng; Xiao, Yin; Hu, Yun; Sun, Haiye; Xue, Wei; Zhang, Liang; Shi, Gui-Yang

    2016-09-01

    Dissection of the hereditary architecture underlying Saccharomyces cerevisiae tolerance to acetic acid is essential for ethanol fermentation. In this work, a genomics approach was used to dissect hereditary variations in acetic acid tolerance between two phenotypically different strains. A total of 160 segregants derived from these two strains were obtained. Phenotypic analysis indicated that the acetic acid tolerance displayed a normal distribution in these segregants, and suggested that the acetic acid tolerant traits were controlled by multiple quantitative trait loci (QTLs). Thus, 220 SSR markers covering the whole genome were used to detect QTLs of acetic acid tolerant traits. As a result, three QTLs were located on chromosomes 9, 12, and 16, respectively, which explained 38.8-65.9 % of the range of phenotypic variation. Furthermore, twelve genes of the candidates fell into the three QTL regions by integrating the QTL analysis with candidates of acetic acid tolerant genes. These results provided a novel avenue to obtain more robust strains. PMID:27430512

  16. Mixed phenotype acute leukemia

    Institute of Scientific and Technical Information of China (English)

    Ye Zixing; Wang Shujie

    2014-01-01

    Objective To highlight the current understanding of mixed phenotype acute leukemia (MPAL).Data sources We collected the relevant articles in PubMed (from 1985 to present),using the terms "mixed phenotype acute leukemia","hybrid acute leukemia","biphenotypic acute leukemia",and "mixed lineage leukemia".We also collected the relevant studies in WanFang Data base (from 2000 to present),using the terms "mixed phenotype acute leukemia" and "hybrid acute leukemia".Study selection We included all relevant studies concerning mixed phenotype acute leukemia in English and Chinese version,with no limitation of research design.The duplicated articles are excluded.Results MPAL is a rare subgroup of acute leukemia which expresses the myeloid and lymphoid markers simultaneously.The clinical manifestations of MPAL are similar to other acute leukemias.The World Health Organization classification and the European Group for Immunological classification of Leukaemias 1998 cdteria are most widely used.MPAL does not have a standard therapy regimen.Its treatment depends mostly on the patient's unique immunophenotypic and cytogenetic features,and also the experience of individual physician.The lack of effective treatment contributes to an undesirable prognosis.Conclusion Our understanding about MPAL is still limited.The diagnostic criteria have not been unified.The treatment of MPAL remains to be investigated.The prognostic factor is largely unclear yet.A better diagnostic cdteria and targeted therapeutics will improve the therapy effect and a subsequently better prognosis.

  17. Phenotypic Resistance to Antibiotics

    Directory of Open Access Journals (Sweden)

    Jose L. Martinez

    2013-04-01

    Full Text Available The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented.

  18. Fault Tolerant Feedback Control

    DEFF Research Database (Denmark)

    Stoustrup, Jakob; Niemann, H.

    2001-01-01

    An architecture for fault tolerant feedback controllers based on the Youla parameterization is suggested. It is shown that the Youla parameterization will give a residual vector directly in connection with the fault diagnosis part of the fault tolerant feedback controller. It turns out that there...... is a separation be-tween the feedback controller and the fault tolerant part. The closed loop feedback properties are handled by the nominal feedback controller and the fault tolerant part is handled by the design of the Youla parameter. The design of the fault tolerant part will not affect the...... design of the nominal feedback con-troller....

  19. Mechanical tolerance stackup and analysis

    CERN Document Server

    Fischer, Bryan R

    2004-01-01

    BackgroundDimensioning and TolerancingTolerance Format and Decimal PlacesConverting Plus/Minus Dimensions and Tolerances into Equal Bilaterally Toleranced DimensionsVariation and Sources of VariationTolerance AnalysisWorst-case Tolerance StackupsStatistical Tolerance StackupsGeometric Dimensioning and Tolerancing (GD&T)Converting Plus/Minus Tolerancing to Positional Tolerancing and Projected Tolerance ZonesDiametral and Radial Tolerance StackupsSpecifying Material Condition Modifiers and Their Effect on Tolerance Stackups The Tolerance Stackup SketchThe Tolerance Stackup Report FormTolerance S

  20. QTLs for tolerance of drought and breeding for tolerance of abiotic and biotic stress: an integrated approach.

    Directory of Open Access Journals (Sweden)

    Shalabh Dixit

    Full Text Available BACKGROUND: The coupling of biotic and abiotic stresses leads to high yield losses in rainfed rice (Oryza sativa L. growing areas. While several studies target these stresses independently, breeding strategies to combat multiple stresses seldom exist. This study reports an integrated strategy that combines QTL mapping and phenotypic selection to develop rice lines with high grain yield (GY under drought stress and non-stress conditions, and tolerance of rice blast. METHODOLOGY: A blast-tolerant BC2F3-derived population was developed from the cross of tropical japonica cultivar Moroberekan (blast- and drought-tolerant and high-yielding indica variety Swarna (blast- and drought-susceptible through phenotypic selection for blast tolerance at the BC2F2 generation. The population was studied for segregation distortion patterns and QTLs for GY under drought were identified along with study of epistatic interactions for the trait. RESULTS: Segregation distortion, in favour of Moroberekan, was observed at 50 of the 59 loci. Majority of these marker loci co-localized with known QTLs for blast tolerance or NBS-LRR disease resistance genes. Despite the presence of segregation distortion, high variation for DTF, PH and GY was observed and several QTLs were identified under drought stress and non-stress conditions for the three traits. Epistatic interactions were also detected for GY which explained a large proportion of phenotypic variance observed in the population. CONCLUSIONS: This strategy allowed us to identify QTLs for GY along with rapid development of high-yielding purelines tolerant to blast and drought with considerably reduced efforts. Apart from this, it also allowed us to study the effects of the selection cycle for blast tolerance. The developed lines were screened at IRRI and in the target environment, and drought and blast tolerant lines with high yield were identified. With tolerance to two major stresses and high yield potential, these

  1. Emergence of phenotype switching through continuous and discontinuous evolutionary transitions.

    Science.gov (United States)

    Patra, Pintu; Klumpp, Stefan

    2015-07-01

    Bacterial persistence (phenotypic tolerance to antibiotics) provides a prime example of bet-hedging, where normally growing cells generate slow-growing but antibiotic-tolerant persister cells to survive through periods of exposure to antibiotics. The population dynamics of persistence is explained by a phenotype switching mechanism that allows individual cells to switch between these different cellular states with different environmental sensitivities. Here, we perform a theoretical study based on an exact solution for the case of a periodic variation of the environment to address how phenotype switching emerges and under what conditions switching is or is not beneficial for long-time growth. Specifically we report a bifurcation through which a fitness maximum and minimum emerge above a threshold in the duration of exposure to the antibiotic. Only above this threshold, the optimal phenotype switching rates are adjusted to the time scales of the environment, as emphasized by previous theoretical studies, while below the threshold a non-switching population is fitter than a switching one. The bifurcation can be of different type, depending on how the phenotype switching rates are allowed to vary. If the switching rates for both directions of the switch are coupled, the transition is discontinuous and results in evolutionary hysteresis, which we confirm with a stochastic simulation. If the switching rates vary individually, a continuous transition is obtained and no hysteresis is found. We discuss how both scenarios can be linked to changes in the underlying molecular networks. PMID:26020274

  2. 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

  3. 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...

  4. Phenotypic Switching in Fungi

    OpenAIRE

    Jain, Neena; Hasan, Fahmi; Fries, Bettina C.

    2008-01-01

    Over the past three decades new fungal diseases have emerged that now constitute a major threat, especially for patients with chronic diseases and/or underlying immune defi ciencies. Despite the epidemiologic data, the emergence of stable drug-resistant or hyper-virulent fungal strains in human disease has not been demonstrated as seen in emerging viral and bacterial infections. Fungi are eukaryotic microbes that capitalize on a sophisticated built-in ability to generate phenotypic variabilit...

  5. Aluminum tolerance association mapping in triticale

    Directory of Open Access Journals (Sweden)

    Niedziela Agnieszka

    2012-02-01

    Full Text Available Abstract Background Crop production practices and industrialization processes result in increasing acidification of arable soils. At lower pH levels (below 5.0, aluminum (Al remains in a cationic form that is toxic to plants, reducing growth and yield. The effect of aluminum on agronomic performance is particularly important in cereals like wheat, which has promoted the development of programs directed towards selection of tolerant forms. Even in intermediately tolerant cereals (i.e., triticale, the decrease in yield may be significant. In triticale, Al tolerance seems to be influenced by both wheat and rye genomes. However, little is known about the precise chromosomal location of tolerance-related genes, and whether wheat or rye genomes are crucial for the expression of that trait in the hybrid. Results A mapping population consisting of 232 advanced breeding triticale forms was developed and phenotyped for Al tolerance using physiological tests. AFLP, SSR and DArT marker platforms were applied to obtain a sufficiently large set of molecular markers (over 3000. Associations between the markers and the trait were tested using General (GLM and Multiple (MLM Linear Models, as well as the Statistical Machine Learning (SML approach. The chromosomal locations of candidate markers were verified based on known assignments of SSRs and DArTs or by using genetic maps of rye and triticale. Two candidate markers on chromosome 3R and 9, 15 and 11 on chromosomes 4R, 6R and 7R, respectively, were identified. The r2 values were between 0.066 and 0.220 in most cases, indicating a good fit of the data, with better results obtained with the GML than the MLM approach. Several QTLs on rye chromosomes appeared to be involved in the phenotypic expression of the trait, suggesting that rye genome factors are predominantly responsible for Al tolerance in triticale. Conclusions The Diversity Arrays Technology was applied successfully to association mapping studies

  6. 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

  7. 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...

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    Mette L Schousboe

    2015-11-01

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

  11. Toleration and its enemies

    DEFF Research Database (Denmark)

    Jarvad, Ib Martin

    2010-01-01

    After a presentation of the development of freedom of expression in Danish constitutional law, to freedom of the press in European human rights law - the Jersild case- to a right to mock and ridicule other faiths in recent Danish practice, the essay of Locke on toleration is examined, its...... background in arminist protestant theology of toleration considered, its conclusion that only faiths that demand allegiance and obedience to foreign powers can be excluded from toleration is highlighted....

  12. State, religion and toleration

    DEFF Research Database (Denmark)

    Huggler, Jørgen

    underline not only the broadmindedness and liberty of individuals or of groups, but also the relevant distinctions and arguments in political philosophy, epistemology, philosophy of religion and philosophical anthropology and their connection with educational issues. Through a discussion of these relations......, the essay argues three theses: (1) Toleration is not reducible to an ethics of spiritual freedom. (2) Toleration is not neutral to fanatism. (3) Toleration involves esteem for the person....

  13. Comprehensive phenotypic analysis of rice (Oryza sativa) response to salinity stress

    KAUST Repository

    Pires, Inês S.

    2015-07-22

    Increase in soil salinity levels is becoming a major cause of crop yield losses worldwide. Rice (Oryza sativa) is the most salt-sensitive cereal crop, and many studies have focused on rice salinity tolerance, but a global understanding of this crop\\'s response to salinity is still lacking. We systematically analyzed phenotypic data previously collected for 56 rice genotypes to assess the extent to which rice uses three known salinity tolerance mechanisms: shoot-ion independent tolerance (or osmotic tolerance), ion exclusion, and tissue tolerance. In general, our analyses of different phenotypic traits agree with results of previous rice salinity tolerance studies. However, we also established that the three salinity tolerance mechanisms mentioned earlier appear among rice genotypes and that none of them is predominant. Against the pervasive view in the literature that the K+/Na+ ratio is the most important trait in salinity tolerance, we found that the K+ concentration was not significantly affected by salt stress in rice, which puts in question the importance of K+/Na+ when analyzing rice salt stress response. Not only do our results contribute to improve our global understanding of salt stress response in an important crop, but we also use our results together with an extensive literature research to highlight some issues commonly observed in salinity stress tolerance studies and to propose solutions for future experiments.

  14. MERICAN CULTURAL TOLERANCE

    Institute of Scientific and Technical Information of China (English)

    ZHANG RUIXIAO

    2014-01-01

    As an emigrant country, the essential characteristic of America culture is its tolerance. It contributes to the formation the diversity of American culture. By tracing back to American history, this essay shows what caused American cultural tolerance. Through describing briefly the manifestation of American cultural tolerance from certain aspects and analyzing the major factors, it will give us a clue about the reason why America can be always prosperous. At last, the paper shows the limitation as well as advantages about the tolerance from the point of current status.

  15. Intraspecific competition facilitates the evolution of tolerance to insect damage in the perennial plant Solanum carolinense.

    Science.gov (United States)

    McNutt, David W; Halpern, Stacey L; Barrows, Kahaili; Underwood, Nora

    2012-12-01

    Tolerance to herbivory (the degree to which plants maintain fitness after damage) is a key component of plant defense, so understanding how natural selection and evolutionary constraints act on tolerance traits is important to general theories of plant-herbivore interactions. These factors may be affected by plant competition, which often interacts with damage to influence trait expression and fitness. However, few studies have manipulated competitor density to examine the evolutionary effects of competition on tolerance. In this study, we tested whether intraspecific competition affects four aspects of the evolution of tolerance to herbivory in the perennial plant Solanum carolinense: phenotypic expression, expression of genetic variation, the adaptive value of tolerance, and costs of tolerance. We manipulated insect damage and intraspecific competition for clonal lines of S. carolinense in a greenhouse experiment, and measured tolerance in terms of sexual and asexual fitness components. Compared to plants growing at low density, plants growing at high density had greater expression of and genetic variation in tolerance, and experienced greater fitness benefits from tolerance when damaged. Tolerance was not costly for plants growing at either density, and only plants growing at low density benefited from tolerance when undamaged, perhaps due to greater intrinsic growth rates of more tolerant genotypes. These results suggest that competition is likely to facilitate the evolution of tolerance in S. carolinense, and perhaps in other plants that regularly experience competition, while spatio-temporal variation in density may maintain genetic variation in tolerance. PMID:22684886

  16. COPD: Definition and Phenotypes

    DEFF Research Database (Denmark)

    Vestbo, J.

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is currently defined as a common preventable and treatable disease that is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious...... particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. The evolution of this definition and the diagnostic criteria currently in use are discussed. COPD is increasingly divided in subgroups or phenotypes based on specific features and association with...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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

  2. Fault tolerant computing systems

    International Nuclear Information System (INIS)

    Fault tolerance involves the provision of strategies for error detection damage assessment, fault treatment and error recovery. A survey is given of the different sorts of strategies used in highly reliable computing systems, together with an outline of recent research on the problems of providing fault tolerance in parallel and distributed computing systems. (orig.)

  3. Moving Beyond Tolerance.

    Science.gov (United States)

    Cirone, Bill

    2001-01-01

    Operating under the umbrella of the Santa Barbara County Education Office, the Beyond Tolerance Educational Center serves as a resource for educators. It provides county schools with information and programs that promote social awareness and tolerance while teaching kids the dangers of hatred and discrimination. (MLH)

  4. Root Traits and Phenotyping Strategies for Plant Improvement

    Science.gov (United States)

    Paez-Garcia, Ana; Motes, Christy M.; Scheible, Wolf-Rüdiger; Chen, Rujin; Blancaflor, Elison B.; Monteros, Maria J.

    2015-01-01

    Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics) and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs. PMID:27135332

  5. Root Traits and Phenotyping Strategies for Plant Improvement

    Directory of Open Access Journals (Sweden)

    Ana Paez-Garcia

    2015-06-01

    Full Text Available Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs.

  6. Tolerance of staphylococci to bactericidal antibiotics.

    Science.gov (United States)

    Vaudaux, Pierre; Lew, Daniel P

    2006-05-01

    Antibiotic therapy for deep-seated staphylococcal infections, especially when they are associated with artificial devices used for orthopedic surgery is often associated with failure. Standard anti-staphylococcal bactericidal antibiotics, such as semi-synthetic penicillins, cephalosporins, or glycopeptides, are effective when given prophylactically in clinical conditions or experimental trials of implant-related infections. However, the efficacy of all anti-staphylococcal agents is seriously diminished on already established implant-related deep-seated infections, which then frequently require surgical implant removal to obtain a cure. The failure of antibiotic therapy to cure established staphylococcal foreign-body infections may arise in part from a broad-spectrum phenotypic tolerance expressed in vivo to different classes of antimicrobial agents. The molecular and physiological mechanisms of this in vivo tolerance remain poorly understood. PMID:16651066

  7. Identification for Heat Tolerance in Backcross Recombinant Lines and Screening of Backcross Introgression Lines with Heat Tolerance at Milky Stage in Rice

    Institute of Scientific and Technical Information of China (English)

    LIAO Jiang-lin; ZHANG Hong-yu; SHAO Xue-lian; ZHONG Ping-an; HUANG Ying-jin

    2011-01-01

    The present study aimed at breeding new rice germplasms with similar genome but significantly differed in heat tolerance during the grain filling stage.A total of 791 BC1F8 backcross recombinant lines,derived from the cross of Xieqingzao B / N22∥Xieqingzao B,were used as materials.Each rice line was separated evenly into two groups,and the heat tolerance of all rice lines were evaluated at natural high temperature in fields.The rice lines with heat tolerant index higher than 90% or lower than 40% were selected to compare the phenotypic characters and further identify heat tolerance at the early milky stage in a phytotron.Rice lines with similar phenotypic characters but significantly differed in heat tolerance at the milky stage were analyzed by 887 simple sequence repeat markers that were evenly distributed on the 12 rice chromosomes.In the result,12 (6 pairs) rice lines with similar phenotypic characters but significantly differed in heat tolerance at the milky stage were obtained.Molecular marker analysis indicated that the genomic polymorphism between 703T and 704S was the smallest in the 6 pairs of rice lines,with only 16 polymorphic sites,including 22 different alleles.The application of these two backcross introgression rice lines for future study on the mechanisms of heat tolerance in rice at the milky stage will be theoretically beneficial in reducing the interference caused by genetic differences from experimental materials.

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

    Directory of Open Access Journals (Sweden)

    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

  9. 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

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

    Science.gov (United States)

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

    2016-01-01

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P 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

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

    Directory of Open Access Journals (Sweden)

    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

  12. Pseudomonas Aeruginosa Resistance Phenotypes and Phenotypic Highlighting Methods

    Science.gov (United States)

    BĂLĂŞOIU, MARIA; BĂLĂŞOIU, A.T.; MĂNESCU, RODICA; AVRAMESCU, CARMEN; IONETE, OANA

    2014-01-01

    Pseudomonas aeruginosa genus bacteria are well known for their increased drug resistance (phenotypic ang genotypic resistance). The most important resistance mechanisms are: enzyme production, reduction of pore expression, reduction of the external membrane proteins expression, efflux systems, topoisomerase mutations. These mechanisms often accumulate and lead to multidrug ressitance strains emergence. The most frequent acquired resistance mechanisms are betalactamase-type enzyme production (ESBLs, AmpC, carbapenemases), which determine variable phenotypes of betalactamines resistance, phenotypes which are associated with aminoglycosides and quinolones resistance. The nonenzymatic drug resistance mechanisms are caused by efflux systems, pore reduction and penicillin-binding proteins (PBP) modification, which are often associated to other resistance mechanisms. Phenotypic methods used for testing these mechanisms are based on highlighting these phenotypes using Kirby Bauer antibiogram, clinical breakpoints, and “cut off” values recommended by EUCAST 2013 standard, version 3.1. PMID:25729587

  13. DNA damage tolerance.

    Science.gov (United States)

    Branzei, Dana; Psakhye, Ivan

    2016-06-01

    Accurate chromosomal DNA replication is fundamental for optimal cellular function and genome integrity. Replication perturbations activate DNA damage tolerance pathways, which are crucial to complete genome duplication as well as to prevent formation of deleterious double strand breaks. Cells use two general strategies to tolerate lesions: recombination to a homologous template, and trans-lesion synthesis with specialized polymerases. While key players of these processes have been outlined, much less is known on their choreography and regulation. Recent advances have uncovered principles by which DNA damage tolerance is regulated locally and temporally - in relation to replication timing and cell cycle stage -, and are beginning to elucidate the DNA dynamics that mediate lesion tolerance and influence chromosome structure during replication. PMID:27060551

  14. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2013-01-01

    be based on a modus vivendi designed to secure peaceful co-existence, but should be based on moral reasons. Forst therefore advances what he calls the ‘respect conception’ of toleration as an in itself morally desirable type of relationship, which is furthermore the only conception of toleration that...... avoids various so-called ‘paradoxes of toleration’. The paper first examines whether Forst’s respect conception can be applied descriptively to distinguish between actual patterns of behaviour and classify different acts of toleration. Then the focus is shifted to toleration out of respect as a normative...... prescription, which Forst presents as a requirement of justice. At both levels, it is argued that Forst’s respect conception is problematic since it presupposes that answers to very substantial normative questions, which are precisely what people tend to disagree on under conditions of pluralism, are already...

  15. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    be based on a modus vivendi designed to secure peaceful co-existence, but should be based on moral reasons. Forst therefore advances what he calls the ‘respect conception’ of toleration as an in itself morally desirable type of relationship, which is furthermore the only conception of toleration that...... avoids various so-called ‘paradoxes of toleration’. The paper first examines whether Forst’s respect conception can be applied descriptively to distinguish between actual patterns of behaviour and classify different acts of toleration. Then the focus is shifted to toleration out of respect as a normative...... prescription, which Forst presents as a requirement of justice. At both levels, it is argued that Forst’s respect conception is problematic since it presupposes that answers to very substantial normative questions, which are precisely what people tend to disagree on under conditions of pluralism, are already...

  16. Fault Tolerant Software Architectures

    OpenAIRE

    Saridakis, Titos; Issarny, Valérie

    1998-01-01

    Coping explicitly with failures during the conception and the design of software development complicates significantly the designer's job. The design complexity leads to software descriptions difficult to understand, which have to undergo many simplifications until their first functioning version. To support the systematic development of complex, fault tolerant software, this paper proposes a layered framework for the analysis of the fault tolerance software properties, where the top-most lay...

  17. Software fault tolerance

    OpenAIRE

    Strigini, Lorenzo

    1990-01-01

    Software design faults are a cause of major concern, and their relative importance is growing as techniques for tolerating hardware faults gain wider acceptance. The application of fault tolerance to design faults is both increasing, in particular in some life-critical applications, and controversial, due to the imperfect state of knowledge about it. This paper surveys the existing applications and research results, to help the reader form an initial picture of the existing possibilities, and...

  18. Tolerance Induction in Liver

    OpenAIRE

    M.H Karimi; Geramizadeh, B; Malek-Hosseini, S. A.

    2015-01-01

    Liver is an exclusive anatomical and immunological organ that displays a considerable tolerance effect. Liver allograft acceptance is shown to occur spontaneously within different species. Although in human transplant patients tolerance is rarely seen, the severity level and cellular mechanisms of transplant rejection vary. Non-paranchymal liver cells, including Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and resident dendritic cells may participate in liver tol...

  19. 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

  20. Sex hormone binding globulin phenotypes

    DEFF Research Database (Denmark)

    Cornelisse, M M; Bennett, Patrick; Christiansen, M;

    1994-01-01

    Human sex hormone binding globulin (SHBG) is encoded by a normal and a variant allele. The resulting SHBG phenotypes (the homozygous normal SHBG, the heterozygous SHBG and the homozygous variant SHBG phenotype) can be distinguished by their electrophoretic patterns. We developed a novel detection...

  1. 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...

  2. Emerging molecular phenotypes of asthma.

    Science.gov (United States)

    Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E

    2015-01-15

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  3. Plant Phenotype Characterization System

    Energy Technology Data Exchange (ETDEWEB)

    Daniel W McDonald; Ronald B Michaels

    2005-09-09

    This report is the final scientific report for the DOE Inventions and Innovations Project: Plant Phenotype Characterization System, DE-FG36-04GO14334. The period of performance was September 30, 2004 through July 15, 2005. The project objective is to demonstrate the viability of a new scientific instrument concept for the study of plant root systems. The root systems of plants are thought to be important in plant yield and thus important to DOE goals in renewable energy sources. The scientific study and understanding of plant root systems is hampered by the difficulty in observing root activity and the inadequacy of existing root study instrumentation options. We have demonstrated a high throughput, non-invasive, high resolution technique for visualizing plant root systems in-situ. Our approach is based upon low-energy x-ray radiography and the use of containers and substrates (artificial soil) which are virtually transparent to x-rays. The system allows us to germinate and grow plant specimens in our containers and substrates and to generate x-ray images of the developing root system over time. The same plant can be imaged at different times in its development. The system can be used for root studies in plant physiology, plant morphology, plant breeding, plant functional genomics and plant genotype screening.

  4. Differential gene expression of two extreme honey bee (Apis mellifera) colonies showing varroa tolerance and susceptibility.

    Science.gov (United States)

    Jiang, S; Robertson, T; Mostajeran, M; Robertson, A J; Qiu, X

    2016-06-01

    Varroa destructor, an ectoparasitic mite of honey bees (Apis mellifera), is the most serious pest threatening the apiculture industry. In our honey bee breeding programme, two honey bee colonies showing extreme phenotypes for varroa tolerance/resistance (S88) and susceptibility (G4) were identified by natural selection from a large gene pool over a 6-year period. To investigate potential defence mechanisms for honey bee tolerance to varroa infestation, we employed DNA microarray and real time quantitative (PCR) analyses to identify differentially expressed genes in the tolerant and susceptible colonies at pupa and adult stages. Our results showed that more differentially expressed genes were identified in the tolerant bees than in bees from the susceptible colony, indicating that the tolerant colony showed an increased genetic capacity to respond to varroa mite infestation. In both colonies, there were more differentially expressed genes identified at the pupa stage than at the adult stage, indicating that pupa bees are more responsive to varroa infestation than adult bees. Genes showing differential expression in the colony phenotypes were categorized into several groups based on their molecular functions, such as olfactory signalling, detoxification processes, exoskeleton formation, protein degradation and long-chain fatty acid metabolism, suggesting that these biological processes play roles in conferring varroa tolerance to naturally selected colonies. Identification of differentially expressed genes between the two colony phenotypes provides potential molecular markers for selecting and breeding varroa-tolerant honey bees. PMID:26919127

  5. Phenotypic plasticity, costs of phenotypes, and costs of plasticity

    DEFF Research Database (Denmark)

    Callahan, Hilary S; Maughan, Heather; Steiner, Uli

    2008-01-01

    Why are some traits constitutive and others inducible? The term costs often appears in work addressing this issue but may be ambiguously defined. This review distinguishes two conceptually distinct types of costs: phenotypic costs and plasticity costs. Phenotypic costs are assessed from patterns of...... covariation, typically between a focal trait and a separate trait relevant to fitness. Plasticity costs, separable from phenotypic costs, are gauged by comparing the fitness of genotypes with equivalent phenotypes within two environments but differing in plasticity and fitness. Subtleties associated with both...... types of costs are illustrated by a body of work addressing predator-induced plasticity. Such subtleties, and potential interplay between the two types of costs, have also been addressed, often in studies involving genetic model organisms. In some instances, investigators have pinpointed the mechanistic...

  6. Escaping the tolerance trap

    International Nuclear Information System (INIS)

    In order to examine the implications of the weakening of OPEC's responsiveness in adjusting its production levels, this paper explicitly incorporates rigidity in the quantity adjustment mechanism, thereby extending previous research which assumed smooth quantity adjustments. The rigidity is manifested in a tolerance range for the discrepancy between the declared target price and that of the market. This environment gives rise to a 'tolerance trap' which impedes the convergence process and inevitably brings the market to a standstill before its reaches the targeted price and revenue objectives. OPEC's reaction to the standstill has important implications for the achievement of the target-based equilibrium and for the potential collapse of the market price. This paper examines OPEC's policy options in the tolerance trap and reveals that the optional policy in order to break this impasse and move closer to the equilibrium point is gradually to reduce output and not to flood the market. (Author)

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

    Directory of Open Access Journals (Sweden)

    Felger Ingrid

    2010-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Ronn Anita

    2011-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Saito-Nakano Yumiko

    2011-12-01

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

  10. Myeloid-derived suppressor cells: Natural regulators for transplant tolerance

    OpenAIRE

    Boros, Peter; Ochando, Jordi C.; Chen, Shu-hsia; Bromberg, Jonathan S.

    2010-01-01

    Myeloid derived suppressor cells (MDSC) contribute to the negative regulation of immune response in cancer patients. This review summarizes results on important issues related to MDSC biology, including expansion and activation of MDSC, phenotype, and subsets as well pathways and different mechanisms by which these cells exert their suppressive effect. Recent observations suggesting that MDSC may have roles in transplant tolerance are presented. Although therapeutic targeting and destruction ...

  11. Inequality, Tolerance, and Growth

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequality...... are measured. Results show that inequality reduces growth but more so in societies where people perceive it as being relatively unfair. Further results indicate that legal quality and social trust are likely transmission channels for the effects of inequality....

  12. Inequality, Tolerance, and Growth

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2004-01-01

    This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequality...... are measured. Results show that inequality reduces growth but more so in societies where people perceive it as being relatively unfair. Further results indicate that legal quality and social trust are likely transmission channels for the effects of inequality....

  13. Epigenetics in heart failure phenotypes.

    Science.gov (United States)

    Berezin, Alexander

    2016-12-01

    Chronic heart failure (HF) is a leading clinical and public problem posing a higher risk of morbidity and mortality in different populations. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved left ventricular ejection fraction (HFpEF). Although both HF phenotypes can be distinguished through clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context, investigation of various molecular and cellular mechanisms leading to the development and progression of both HF phenotypes is very important. There is emerging evidence that epigenetic regulation may have a clue in the pathogenesis of HF. This review represents current available evidence regarding the implication of epigenetic modifications in the development of different HF phenotypes and perspectives of epigenetic-based therapies of HF. PMID:27335803

  14. Capturing phenotypes for precision medicine.

    Science.gov (United States)

    Robinson, Peter N; Mungall, Christopher J; Haendel, Melissa

    2015-10-01

    Deep phenotyping followed by integrated computational analysis of genotype and phenotype is becoming ever more important for many areas of genomic diagnostics and translational research. The overwhelming majority of clinical descriptions in the medical literature are available only as natural language text, meaning that searching, analysis, and integration of medically relevant information in databases such as PubMed is challenging. The new journal Cold Spring Harbor Molecular Case Studies will require authors to select Human Phenotype Ontology terms for research papers that will be displayed alongside the manuscript, thereby providing a foundation for ontology-based indexing and searching of articles that contain descriptions of phenotypic abnormalities-an important step toward improving the ability of researchers and clinicians to get biomedical information that is critical for clinical care or translational research. PMID:27148566

  15. Finding our way through phenotypes.

    Directory of Open Access Journals (Sweden)

    Andrew R Deans

    2015-01-01

    Full Text Available Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.

  16. Next-generation phenotypic screening.

    Science.gov (United States)

    Warchal, Scott J; Unciti-Broceta, Asier; Carragher, Neil O

    2016-07-01

    Phenotypic drug discovery (PDD) strategies are defined by screening and selection of hit or lead compounds based on quantifiable phenotypic endpoints without prior knowledge of the drug target. We outline the challenges associated with traditional phenotypic screening strategies and propose solutions and new opportunities to be gained by adopting modern PDD technologies. We highlight both historical and recent examples of approved drugs and new drug candidates discovered by modern phenotypic screening. Finally, we offer a prospective view of a new era of PDD underpinned by a wealth of technology advances in the areas of in vitro model development, high-content imaging and image informatics, mechanism-of-action profiling and target deconvolution. PMID:27357617

  17. Finding our way through phenotypes.

    Science.gov (United States)

    Deans, Andrew R; Lewis, Suzanna E; Huala, Eva; Anzaldo, Salvatore S; Ashburner, Michael; Balhoff, James P; Blackburn, David C; Blake, Judith A; Burleigh, J Gordon; Chanet, Bruno; Cooper, Laurel D; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E; Dumontier, Michel; Franz, Nico M; Friedrich, Frank; Gkoutos, George V; Haendel, Melissa; Harmon, Luke J; Hayamizu, Terry F; He, Yongqun; Hines, Heather M; Ibrahim, Nizar; Jackson, Laura M; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J; Le Novère, Nicolas; Lundberg, John G; Macklin, James; Mast, Austin R; Midford, Peter E; Mikó, István; Mungall, Christopher J; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J; Richter, Stefan; Robinson, Peter N; Ruttenberg, Alan; Schulz, Katja S; Segerdell, Erik; Seltmann, Katja C; Sharkey, Michael J; Smith, Aaron D; Smith, Barry; Specht, Chelsea D; Squires, R Burke; Thacker, Robert W; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D; Vogt, Lars; Wall, Christine E; Walls, Ramona L; Westerfeld, Monte; Wharton, Robert A; Wirkner, Christian S; Woolley, James B; Yoder, Matthew J; Zorn, Aaron M; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. PMID:25562316

  18. QTLs for Tolerance of Drought and Breeding for Tolerance of Abiotic and Biotic Stress: An Integrated Approach

    OpenAIRE

    Shalabh Dixit; B Emma Huang; Ma Teresa Sta Cruz; Maturan, Paul T; Jhon Christian E Ontoy; Arvind Kumar

    2014-01-01

    BACKGROUND: The coupling of biotic and abiotic stresses leads to high yield losses in rainfed rice (Oryza sativa L.) growing areas. While several studies target these stresses independently, breeding strategies to combat multiple stresses seldom exist. This study reports an integrated strategy that combines QTL mapping and phenotypic selection to develop rice lines with high grain yield (GY) under drought stress and non-stress conditions, and tolerance of rice blast. METHODOLOGY: A blast-tole...

  19. Metabolomic approach for improving ethanol stress tolerance in Saccharomyces cerevisiae.

    Science.gov (United States)

    Ohta, Erika; Nakayama, Yasumune; Mukai, Yukio; Bamba, Takeshi; Fukusaki, Eiichiro

    2016-04-01

    The budding yeast Saccharomyces cerevisiae is widely used for brewing and ethanol production. The ethanol sensitivity of yeast cells is still a serious problem during ethanol fermentation, and a variety of genetic approaches (e.g., random mutant screening under selective pressure of ethanol) have been developed to improve ethanol tolerance. In this study, we developed a strategy for improving ethanol tolerance of yeast cells based on metabolomics as a high-resolution quantitative phenotypic analysis. We performed gas chromatography-mass spectrometry analysis to identify and quantify 36 compounds on 14 mutant strains including knockout strains for transcription factor and metabolic enzyme genes. A strong relation between metabolome of these mutants and their ethanol tolerance was observed. Data mining of the metabolomic analysis showed that several compounds (such as trehalose, valine, inositol and proline) contributed highly to ethanol tolerance. Our approach successfully detected well-known ethanol stress related metabolites such as trehalose and proline thus, to further prove our strategy, we focused on valine and inositol as the most promising target metabolites in our study. Our results show that simultaneous deletion of LEU4 and LEU9 (leading to accumulation of valine) or INM1 and INM2 (leading to reduction of inositol) significantly enhanced ethanol tolerance. This study shows the potential of the metabolomic approach to identify target genes for strain improvement of S. cerevisiae with higher ethanol tolerance. PMID:26344121

  20. Stem Xylem Characterization for Vitis Drought Tolerance.

    Science.gov (United States)

    Rustioni, Laura; Ciacciulli, Angelo; Grossi, Daniele; Brancadoro, Lucio; Failla, Osvaldo

    2016-07-01

    Together with stomatal conductance and root conductivity, the stem water reserve and transport systems could be regulatory mechanisms able to participate in the regulation of the plant water status. Lianas, such as Vitis spp., minimize the trunk support role, and stems have evolved to improve their ability in water transport. In this work, stems of 10 different Vitis species were studied in relation to their expected drought tolerance using reflectance spectroscopy. Spectra were measured before (T0) and after coloration with Sudan IV dye. The T0 spectral signature showed characteristic species features. The partial least squares (PLS) regression and the self-organizing map (SOM) neural network analysis were able to predict the expected drought tolerance score; thus, reflectance spectroscopy was demonstrated to be a useful technique for drought tolerance phenotyping. These methods could be applied for the preliminary selection of new rootstocks/cultivars. Wood composition variation appeared to be correlated with the water stress susceptibility. To clarify this relationship, the attention was focused on the wood hydrophobicity. Sudan IV is a microscopy dye traditionally used to underline suberin, waxes, and, in general, hydrophobic substances. Differences between rough and colored spectra evidenced the absorption band of Sudan IV with a maximum at 539 nm. The coloration intensity was used to develop a hydrophobicity index. The obtained values were correlated with the expected drought tolerance score. Therefore, hydrophobic compounds seem to play an important role in water use efficiency, and an hydrophobic barrier in the xylem tissue appears to be a protective mechanism against water stress. PMID:27281116

  1. Tolerant (parallel) Programming

    Science.gov (United States)

    DiNucci, David C.; Bailey, David H. (Technical Monitor)

    1997-01-01

    In order to be truly portable, a program must be tolerant of a wide range of development and execution environments, and a parallel program is just one which must be tolerant of a very wide range. This paper first defines the term "tolerant programming", then describes many layers of tools to accomplish it. The primary focus is on F-Nets, a formal model for expressing computation as a folded partial-ordering of operations, thereby providing an architecture-independent expression of tolerant parallel algorithms. For implementing F-Nets, Cooperative Data Sharing (CDS) is a subroutine package for implementing communication efficiently in a large number of environments (e.g. shared memory and message passing). Software Cabling (SC), a very-high-level graphical programming language for building large F-Nets, possesses many of the features normally expected from today's computer languages (e.g. data abstraction, array operations). Finally, L2(sup 3) is a CASE tool which facilitates the construction, compilation, execution, and debugging of SC programs.

  2. Genetic architecture of winter hardiness and frost tolerance in triticale.

    Directory of Open Access Journals (Sweden)

    Wenxin Liu

    Full Text Available Abiotic stress experienced by autumn-sown crops during winter is of great economic importance as it can have a severe negative impact on yield. In this study, we investigated the genetic architecture of winter hardiness and frost tolerance in triticale. To this end, we used a large mapping population of 647 DH lines phenotyped for both traits in combination with genome-wide marker data. Employing multiple-line cross QTL mapping, we identified nine main effect QTL for winter hardiness and frost tolerance of which six were overlapping between both traits. Three major QTL were identified on chromosomes 5A, 1B and 5R. In addition, an epistasis scan revealed the contribution of epistasis to the genetic architecture of winter hardiness and frost tolerance in triticale. Taken together, our results show that winter hardiness and frost tolerance are complex traits that can be improved by phenotypic selection, but also that genomic approaches hold potential for a knowledge-based improvement of these important traits in elite triticale germplasm.

  3. Validated Fault Tolerant Architectures for Space Station

    Science.gov (United States)

    Lala, Jaynarayan H.

    1990-01-01

    Viewgraphs on validated fault tolerant architectures for space station are presented. Topics covered include: fault tolerance approach; advanced information processing system (AIPS); and fault tolerant parallel processor (FTPP).

  4. 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. ...

  5. 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

  6. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

    Directory of Open Access Journals (Sweden)

    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  7. Heat tolerance in wheat

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari

    As a consequence of global climate change, heat stress together with other abiotic stresses will remain an important determinant of future food security. Wheat (Triticum aestivum L.) is the third most important crop of the world feeding one third of the world population. Being a crop of temperate...... climate, wheat is sensitive to heat stress. We need to understand how our crops will perform in these changing climatic conditions and how we can develop varieties, which are more tolerant. The PhD study focussed on understanding heat tolerance in wheat with a combined approach of plant physiology and...... genetic determination (GD). An initial mass screening of 1,274 wheat cultivars (diverse origin) showed a GD of 8.5%. A stronger heat treatment was given in the second screening with 138 selected cultivars resulting in larger differentiation of cultivars (GD 15.4%). The GD further increased to 27.9% in the...

  8. Abuse Tolerance Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Orendorff, Christopher J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nagasubramanian, Ganesan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Fenton, Kyle R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Allcorn, Eric [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improve lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.

  9. Glucose tolerance test - non-pregnant

    Science.gov (United States)

    Oral glucose tolerance test - non-pregnant; OGTT - non-pregnant; Diabetes - glucose tolerance test ... The most common glucose tolerance test is the oral glucose tolerance test (OGTT). Before the test begins, a sample of blood will be ...

  10. Socially-Tolerable Discrimination

    OpenAIRE

    Amegashie, J. Atsu

    2008-01-01

    History is replete with overt discrimination on the basis of race, gender, age, citizenship, ethnicity, marital status, academic performance, health status, volume of market transactions, religion, sexual orientation, etc. However, these forms of discrimination are not equally tolerable. For example, discrimination based on immutable or prohibitively unalterable characteristics such as race, gender, or ethnicity is much less acceptable. Why? I develop a simple rent-seeking model of conflict w...

  11. Socially-Tolerable Discrimination

    OpenAIRE

    J. Atsu Amegashie

    2008-01-01

    History is replete with overt discrimination of various forms. However, these forms of discrimination are not equally tolerable. For example, discrimination based on immutable or prohibitively unalterable characteristics such as race or gender is much less acceptable. Why? I develop a simple model of conflict which is driven by either racial (gender) discrimination or generational discrimination (i.e., young versus old). I show that there exist parameters of the model where racial (gender) di...

  12. Socially-Tolerable Discrimination

    OpenAIRE

    Amegashie, J. Atsu

    2008-01-01

    History is replete with overt discrimination on the basis of race, gender, age, citizenship, ethnicity, marital status, academic performance, health status, volume of market transactions, religion, sexual orientation, etc. However, these forms of discrimination are not equally tolerable. For example, discrimination based on immutable or prohibitively unalterable characteristics such as race, gender, or ethnicity is much less acceptable. Why? I develop a simple model of conflict which is drive...

  13. Socially-tolerable discrimination

    OpenAIRE

    Amegashie, J. Atsu

    2008-01-01

    History is replete with overt discrimination on the basis of race, gender, age, citizenship, ethnicity, marital status, academic performance, health status, volume of market transactions, religion, sexual orientation, etc. However, these forms of discrimination are not equally tolerable. For example, discrimination based on immutable or prohibitively unalterable characteristics such as race, gender, or ethnicity is much less acceptable. Why? I develop a simple rent-seeking model of conflict w...

  14. Phenotypic MicroRNA Microarrays

    Directory of Open Access Journals (Sweden)

    Veronica Soloveva

    2013-04-01

    Full Text Available Microarray technology has become a very popular approach in cases where multiple experiments need to be conducted repeatedly or done with a variety of samples. In our lab, we are applying our high density spots microarray approach to microscopy visualization of the effects of transiently introduced siRNA or cDNA on cellular morphology or phenotype. In this publication, we are discussing the possibility of using this micro-scale high throughput process to study the role of microRNAs in the biology of selected cellular models. After reverse-transfection of microRNAs and siRNA, the cellular phenotype generated by microRNAs regulated NF-κB expression comparably to the siRNA. The ability to print microRNA molecules for reverse transfection into cells is opening up the wide horizon for the phenotypic high content screening of microRNA libraries using cellular disease models.

  15. Exposures exceeding tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Stone, R.S.

    1944-10-25

    This letter was written in 1944 and applies to the amount of radiation a person could be subjected to under emergency, wartime conditions. Mr. Stone recommends to Dr. Norwood that no man should be ordered to expose himself to more than a tolerance dose (0.1r in a 24 hr period) except in the case of an extreme emergency in which time is of the essence. And that before any man is asked to exceed tolerance that a radiation trained physician be called in for consultation. His recommendations to said physician are that: (a) a single exposure of 1r would cause no harm and could be repeated at long intervals, (b) an exposure of 5 to 10r would produce loss of appetite and nausea and would increase the chances of genetic change but would cause no clinically detectable changes after the incident, (C) an exposure of 25r would do the same as (b) but with greater probability -- he would be personally willing to take a 25r exposure to accomplish an extremely important job, (4) in general keep exposures well below tolerance, (5) due to the genetic effects, women of childbearing age and younger men should be subjected to none and lesser amounts of radiation, respectively.

  16. Drought Tolerance in Wheat

    Directory of Open Access Journals (Sweden)

    Arash Nezhadahmadi

    2013-01-01

    Full Text Available Drought is one of the most important phenomena which limit crops’ production and yield. Crops demonstrate various morphological, physiological, biochemical, and molecular responses to tackle drought stress. Plants’ vegetative and reproductive stages are intensively influenced by drought stress. Drought tolerance is a complicated trait which is controlled by polygenes and their expressions are influenced by various environmental elements. This means that breeding for this trait is so difficult and new molecular methods such as molecular markers, quantitative trait loci (QTL mapping strategies, and expression patterns of genes should be applied to produce drought tolerant genotypes. In wheat, there are several genes which are responsible for drought stress tolerance and produce different types of enzymes and proteins for instance, late embryogenesis abundant (lea, responsive to abscisic acid (Rab, rubisco, helicase, proline, glutathione-S-transferase (GST, and carbohydrates during drought stress. This review paper has concentrated on the study of water limitation and its effects on morphological, physiological, biochemical, and molecular responses of wheat with the possible losses caused by drought stress.

  17. Drought tolerance in wheat.

    Science.gov (United States)

    Nezhadahmadi, Arash; Prodhan, Zakaria Hossain; Faruq, Golam

    2013-01-01

    Drought is one of the most important phenomena which limit crops' production and yield. Crops demonstrate various morphological, physiological, biochemical, and molecular responses to tackle drought stress. Plants' vegetative and reproductive stages are intensively influenced by drought stress. Drought tolerance is a complicated trait which is controlled by polygenes and their expressions are influenced by various environmental elements. This means that breeding for this trait is so difficult and new molecular methods such as molecular markers, quantitative trait loci (QTL) mapping strategies, and expression patterns of genes should be applied to produce drought tolerant genotypes. In wheat, there are several genes which are responsible for drought stress tolerance and produce different types of enzymes and proteins for instance, late embryogenesis abundant (lea), responsive to abscisic acid (Rab), rubisco, helicase, proline, glutathione-S-transferase (GST), and carbohydrates during drought stress. This review paper has concentrated on the study of water limitation and its effects on morphological, physiological, biochemical, and molecular responses of wheat with the possible losses caused by drought stress. PMID:24319376

  18. A Multirelational Account of Toleration

    DEFF Research Database (Denmark)

    Ferretti, Maria Paola; Lægaard, Sune

    2013-01-01

    Toleration classically denotes a relation between two agents that is characterised by three components: objection, power, and acceptance overriding the objection. Against recent claims that classical toleration is not applicable in liberal democracies and that toleration must therefore either be...... as wholes, rather than as sets of isolated relations. We explain this by showing how certain cases of toleration are multi-dimensional and how the descriptive concept of toleration might be understood intersectionally. We exemplify this by drawing on case studies of mosque controversies in Germany...

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

    Directory of Open Access Journals (Sweden)

    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.

  20. 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...

  1. 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....

  2. 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

  3. Variation in sulfide tolerance of photosystem II in phylogenetically diverse cyanobacteria from sulfidic habitats

    Science.gov (United States)

    Miller, Scott R.; Bebout, Brad M.

    2004-01-01

    Physiological and molecular phylogenetic approaches were used to investigate variation among 12 cyanobacterial strains in their tolerance of sulfide, an inhibitor of oxygenic photosynthesis. Cyanobacteria from sulfidic habitats were found to be phylogenetically diverse and exhibited an approximately 50-fold variation in photosystem II performance in the presence of sulfide. Whereas the degree of tolerance was positively correlated with sulfide levels in the environment, a strain's phenotype could not be predicted from the tolerance of its closest relatives. These observations suggest that sulfide tolerance is a dynamic trait primarily shaped by environmental variation. Despite differences in absolute tolerance, similarities among strains in the effects of sulfide on chlorophyll fluorescence induction indicated a common mode of toxicity. Based on similarities with treatments known to disrupt the oxygen-evolving complex, it was concluded that sulfide toxicity resulted from inhibition of the donor side of photosystem II.

  4. Leaf segmentation in plant phenotyping

    NARCIS (Netherlands)

    Scharr, Hanno; Minervini, Massimo; French, Andrew P.; Klukas, Christian; Kramer, David M.; Liu, Xiaoming; Luengo, Imanol; Pape, Jean Michel; Polder, Gerrit; Vukadinovic, Danijela; Yin, Xi; Tsaftaris, Sotirios A.

    2016-01-01

    Image-based plant phenotyping is a growing application area of computer vision in agriculture. A key task is the segmentation of all individual leaves in images. Here we focus on the most common rosette model plants, Arabidopsis and young tobacco. Although leaves do share appearance and shape cha

  5. One-Hour plasma glucose identifies insulin resistance and β-cell dysfunction in individuals with normal glucose tolerance: cross-sectional data from the relationship between insulin sensitivity and cardiovascular risk (RISC) study

    OpenAIRE

    Manco, M.; S. Panunzi; Macfarlane, D.Y.; Golay, A.; Melander, O; Konrad, T; Petrie, J. R.; Mingrone, G

    2010-01-01

    OBJECTIVE Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype. RESEARCH DESIGN AND METHODS A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), a...

  6. The possibilities of applying marker assisted selection in breeding boron tolerant wheat

    Directory of Open Access Journals (Sweden)

    Brdar-Jokanović Milka

    2013-01-01

    Full Text Available The aim of this study was to investigate the possibilities of applying molecular markers-microsatellites in breeding boron tolerant wheat. The study comprised the investigation of allelic variability of sixty bread wheat accessions in two microsatellite loci (Xgwm46-7B and Xgwm577-7B for which was assumed that are placed near the 7B chromosome locus involved in the expression of boron tolerance in wheat. Phenotypic variability concerning boron tolerance was assessed via root length reduction of wheat seedlings grown in the presence of high external boron, applied as boric acid solution (concentrations 50, 100 and 150 mg/l, boron treatments B50, B100 and B150. The indication of marker-trait associations was determined by comparing the allelic variability in the two microsatellite loci with the phenotypic variability in boron tolerance. Nonparametric Kruskal-Wallis test was used for the comparisons. The indication of marker-trait association was found for both Xgwm46-7B and Xgwm577-7B; on B150 and B50 treatments, respectively. Allelic forms identified in Xgwm577-7B locus may be related to tolerance, medium tolerance and sensitivity to high boron. This was not the case for Xgwm46-7B, where the identified alleles were related only to boron tolerance and sensitivity. Therefore, Xgwm577-7B may be preferred over Xgwm46-7B when studying boron tolerance in wheat. However, a considerable portion of boron tolerant accessions carried different alleles in the investigated loci, implying boron tolerance as a quantitative trait with more than one chromosomal region involved in its expression. Therefore, the allelic variability of more than the analyzed two loci should be investigated. [Projekat Ministarstva nauke Republike Srbije, br. TR 31066

  7. Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner.

    Science.gov (United States)

    Waller, Tobias; Kesper, Laura; Hirschfeld, Josefine; Dommisch, Henrik; Kölpin, Johanna; Oldenburg, Johannes; Uebele, Julia; Hoerauf, Achim; Deschner, James; Jepsen, Sören; Bekeredjian-Ding, Isabelle

    2016-04-01

    Porphyromonas gingivalisis an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed fromP. gingivalispromote monocyte unresponsiveness to liveP. gingivalisbut retain reactivity to stimulation with bacterial DNA isolated fromP. gingivalisor AIM2 ligand poly(dA·dT). OMV-mediated tolerance ofP. gingivalisis characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness toP. gingivalis; full reactivity toP. gingivaliscan be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition ofP. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4-and not of TLR2-restores responsiveness toP. gingivalis Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose thatP. gingivalisOMV contribute to local immune evasion ofP. gingivalisby hampering the host response. PMID:26857578

  8. A single locus is responsible for salinity tolerance in a Chinese landrace barley (Hordeum vulgare L..

    Directory of Open Access Journals (Sweden)

    Rugen Xu

    Full Text Available INTRODUCTION: Salinity and waterlogging are two major abiotic stresses severely limiting barley production. The lack of a reliable screening method makes it very hard to improve the tolerance through breeding programs. METHODS: This work used 188 DH lines from a cross between a Chinese landrace variety, TX9425 (waterlogging and salinity tolerant, and a Japanese malting barley, Naso Nijo (waterlogging and salinity sensitive, to identify QTLs associated with the tolerance. RESULTS: Four QTLs were found for waterlogging tolerance. The salinity tolerance was evaluated with both a hydroponic system and in potting mixture. In the trial with potting mixture, only one major QTL was identified to associate with salinity tolerance. This QTL explained nearly 50% of the phenotypic variation, which makes it possible for further fine mapping and cloning of the gene. This QTL was also identified in the hydroponic experiment for different salt-related traits. The position of this QTL was located at a similar position to one of the major QTLs for waterlogging tolerance, indicating the possibility of similar mechanisms controlling both waterlogging and salinity tolerance. CONCLUSION: The markers associated with the QTL provided a unique opportunity in breeding programs for selection of salinity and waterlogging tolerance.

  9. Volatile organic compounds as non-invasive markers for plant phenotyping.

    Science.gov (United States)

    Niederbacher, B; Winkler, J B; Schnitzler, J P

    2015-09-01

    Plants emit a great variety of volatile organic compounds (VOCs) that can actively participate in plant growth and protection against biotic and abiotic stresses. VOC emissions are strongly dependent on environmental conditions; the greatest ambiguity is whether or not the predicted change in climate will influence and modify plant-pest interactions that are mediated by VOCs. The constitutive and induced emission patterns between plant genotypes, species, and taxa are highly variable and can be used as pheno(chemo)typic markers to distinguish between different origins and provenances. In recent years significant progress has been made in molecular and genetic plant breeding. However, there is actually a lack of knowledge in functionally linking genotypes and phenotypes, particularly in analyses of plant-environment interactions. Plant phenotyping, the assessment of complex plant traits such as growth, development, tolerance, resistance, etc., has become a major bottleneck, and quantitative information on genotype-environment relationships is the key to addressing major future challenges. With increasing demand to support and accelerate progress in breeding for novel traits, the plant research community faces the need to measure accurately increasingly large numbers of plants and plant traits. In this review article, we focus on the promising outlook of VOC phenotyping as a fast and non-invasive measure of phenotypic dynamics. The basic principle is to define plant phenotypes according to their disease resistance and stress tolerance, which in turn will help in improving the performance and yield of economically relevant plants. PMID:25969554

  10. Fault Tolerant Control Systems

    DEFF Research Database (Denmark)

    Bøgh, S.A.

    from this study highlights requirements for a dedicated software environment for fault tolerant control systems design. The second detailed study addressed the detection of a fault event and determination of the failed component. A variety of algorithms were compared, based on two fault scenarios in...... faults, but also that the research field still misses a systematic approach to handle realistic problems such as low sampling rate and nonlinear characteristics of the system. The thesis contributed with methods to detect both faults and specifically with a novel algorithm for the actuator fault...... detection that is superior in terms of performance and complexity to the other algorithms in the comparative study....

  11. Fault Tolerant Computer Architecture

    CERN Document Server

    Sorin, Daniel

    2009-01-01

    For many years, most computer architects have pursued one primary goal: performance. Architects have translated the ever-increasing abundance of ever-faster transistors provided by Moore's law into remarkable increases in performance. Recently, however, the bounty provided by Moore's law has been accompanied by several challenges that have arisen as devices have become smaller, including a decrease in dependability due to physical faults. In this book, we focus on the dependability challenge and the fault tolerance solutions that architects are developing to overcome it. The two main purposes

  12. The Composition and Metabolic Phenotype of Neisseria gonorrhoeae Biofilms

    Directory of Open Access Journals (Sweden)

    Michael A Apicella

    2011-04-01

    Full Text Available N. gonorrhoeae has been shown to form biofilms during cervical infection. Thus, biofilm formation may play an important role in the infection of women. The ability of N. gonorrhoeae to form membrane blebs is crucial to biofilm formation. Blebs contain DNA and outer membrane structures, which have been shown to be major constituents of the biofilm matrix. The organism expresses a DNA thermonuclease that is involved in remodeling of the biofilm matrix. Comparison of the transcriptional profiles of gonococcal biofilms and planktonic runoff indicate that genes involved in anaerobic metabolism and oxidative stress tolerance are more highly expressed in biofilm. The expression of aniA, ccp, and norB, which encode nitrite reductase, cytochrome c peroxidase, and nitric oxide reductase respectively, is required for mature biofilm formation over glass and human cervical cells. In addition, anaerobic respiration occurs in the substratum of gonococcal biofilms and disruption of the norB gene required for anaerobic respiration, results in a severe biofilm attenuation phenotype. It has been demonstrated that accumulation of nitric oxide (NO contributes to the phenotype of a norB mutant and can retard biofilm formation. However, NO can also enhance biofilm formation, and this is largely dependent on the concentration and donation rate or steady state kinetics of NO. The majority of the genes involved in gonococcal oxidative stress tolerance are also required for normal biofilm formation, as mutations in the following genes result in attenuated biofilm formation over cervical cells and/or glass: oxyR, gor, prx, mntABC, trxB, and estD. Overall, biofilm formation appears to be an adaptation for coping with the environmental stresses present in the female genitourinary tract. Therefore, this review will discuss the studies, which describe the composition and metabolic phenotype of gonococcal biofilms.

  13. Phenotypic constraints and phenotypic hitchhiking in a promiscuous enzyme

    OpenAIRE

    Wagner, Andreas; Weikert, Christian

    2012-01-01

    Covarying phenotypic traits can limit natural selection’s ability to modify these traits. Most evolutionary studies on trait covariation use the comparative method to study complex traits of multicellular organisms. Simpler traits have the advantage of being amenable to experimental evolution. Here we study such a simple molecular system, the TEM-1 beta-lactamase protein, a promiscuous enzyme that hydrolyses antibiotics, and thus confers antibiotic resistance to bacteria. We mutagenized large...

  14. QTLs Analysis of Cold Tolerance During Early Growth Period for Rice

    Institute of Scientific and Technical Information of China (English)

    HE Xiu-ying; HAN Long-zhi; XU Shi-ping; QIAO Yong-li; LIAO Yao-ping; CAO Gui-lan; MAO Xing-xue; ZHANG Yuan-yuan; WENG Ke-nan; AN Yong-ping; CHEN Zhao-ming; YE Jong-doo; CHEN Yue-han; KOH Hee-jong; XIAO Wan-sheng

    2004-01-01

    The quantitative trait loci (QTLs) for cold tolerance during early growth period were identified using a F2:3 population microsatellite markers. The cold tolerance at the seedling and tillering stages, and the growth ability of seedling under low temperature conditions were evaluated. All of the traits associated with cold tolerance at early growth stages appeared a continuous distribution near to normal in F3 lines, these were inherited as quantitative traits controlled by polygenes. Three QTLs on chromosomes 1, 5 and 9, which associated with cold tolerance at the seedling stage were detected. Among them, qCTS1accounted for 15.5% of observed phenotypic variation; Five QTLs on chromosomes 2, 3, 7, 9 and 11, associated with cold tolerance at the tillering stage were found, which explained lower percentage of observed phenotypic variation; Four QTLs on chromosomes 1,2, 11 and 12, which associated with the growth ability of seedling under low temperature conditions were found, among them,qGAS2 and qGAS12 explained 26.6 and 42.9% of observed phenotypic variation, respectively, which were major genes.

  15. Statistical models in agriculture: biometrical methods for evaluating phenotypic stability in plant breeding

    Directory of Open Access Journals (Sweden)

    Daniel Furtado Ferreira

    2006-12-01

    Full Text Available This paper reviews the main concepts of several methods of phenotypic stability analysis and points out their advantages and limitations. It was concluded that the simple linear regression method of Eberhart & Russel (1966 and the bi?segmented regression method of Silva & Barreto (1985 have only historical importance nowadays. Moreover, based on factors discussed in the paper, it is recommended that the regression models of Toler & Burrows (1998 and the Additive Main effects and Multiplicative Interactions (AMMI model should be used simultaneously to study and to estimate phenotypic stability effects.

  16. Ethnopoly promotes tolerance

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    On Friday 23 April, 225 primary school children from the eight schools in Meyrin-Cointrin and their accompanying adults took part in a big game of Ethnopoly. Private individuals, associations, administrations, shopkeepers and CERN all opened their doors to them to talk about their countries, their customs and what they are doing to promote tolerance and integration.   The CERN stand set up at ForumMeyrin for the Ethnopoly game. Scurrying from one place to another, the 10 and 11 year olds were made aware of the rich cultural diversity of their commune, which is home to 130 different nationalities. Physicists and engineers from CERN took up residence in the Forum Meyrin for the day in order to talk to the children about the advantages of international collaboration, a subject dear to the Organization's heart. They welcomed around fifty children in the course of the day, conveying to them a message of tolerance: despite their differences, the 10,000 scientists and other members of the CERN...

  17. Fault-tolerant multiprocessor computer

    Energy Technology Data Exchange (ETDEWEB)

    Smith, T.B. III; Lala, J.H.; Goldberg, J.; Kautz, W.H.; Melliar-Smith, P.M.; Green, M.W.; Levitt, K.N.; Schwartz, R.L.; Weinstock, C.B.; Palumbo, D.L.

    1986-01-01

    The development and evaluation of fault-tolerant computer architectures and software-implemented fault tolerance (SIFT) for use in advanced NASA vehicles and potentially in flight-control systms are described in a collection of previously published reports prepared for NASA. Topics addressed include the principles of fault-tolerant multiprocessor (FTMP) operation; processor and slave regional designs; FTMP executive, facilities, aceptance-test/diagnostic, applications, and support software; FTM reliability and availability models; SIFT hardware design; and SIFT validation and verification.

  18. Carbon Isotope Discrimination and Salinity Tolerance in Rice

    International Nuclear Information System (INIS)

    seedling stage for comparison with results from the reproductive stage. A strong negative correlation between Δ and seedling shoot biomass was observed but not with SES scores, possibly due to this set being less variable than the one used in the first experiment. In Experiment 5, a set of 38 lines which included both near isogenic lines (NILs) and a few RILs with equal tolerant and sensitive lines was evaluated. This experiment aimed to test whether the Pokkali introgressions that affected salinity tolerance from the Saltol QTL also influenced the extent of CID. No significant relationships of Δ with SES scores or with Na+ uptake and Na+: K+ ratios were observed under both saline and non-saline conditions, but Δ correlated negatively with shoot length (R2 = -0.34). Finally in Experiment 6, a set of 80 F2 families from a second mapping population (FL478 / Azucena) was tested at the seedling stage to compare with the original IR29 / Pokkali RIL population results. Here Δ had a weak correlation with seedling vigor and less so with SES scores, and no QTLs above LOD 3.0 were detected for the Δ values using these 80 F2 families, which is probably because these families were still segregating. This also suggests that future studies should rely more on stable lines to allow reliable phenotyping and better correspondence between the genotype and phenotype data. In summary, Δ correlated positively with salinity tolerance in rice, both at the seedling and reproductive stages. However, variation in Δ was greater in more diverse genotypes and the correlations of Δ with salt tolerance became stronger with increasing diversity. Δ could therefore be successfully used for selection of parental lines for breeding. (author)

  19. Commercialization of radiation tolerant camera

    International Nuclear Information System (INIS)

    In this project, radiation tolerant camera which tolerates 106 - 108 rad total dose is developed. In order to develop radiation tolerant camera, radiation effect of camera components was examined and evaluated, and camera configuration was studied. By the result of evaluation, the components were decided and design was performed. Vidicon tube was selected to use by image sensor and non-browning optics and camera driving circuit were applied. The controller needed for CCTV camera system, lens, light, pan/tilt controller, was designed by the concept of remote control. And two type of radiation tolerant camera were fabricated consider to use in underwater environment or normal environment. (author)

  20. The Role of Anti-Müllerian Hormone in the Characterization of the Different Polycystic Ovary Syndrome Phenotypes.

    Science.gov (United States)

    Romualdi, Daniela; Di Florio, C; Tagliaferri, V; De Cicco, S; Gagliano, D; Immediata, V; Lanzone, A; Guido, M

    2016-05-01

    Rotterdam criteria identified 4 polycystic ovary syndrome (PCOS) phenotypes based on the combination of anovulation (ANOV), hyperandrogenism (HA), and polycystic ovaries (PCOs): phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO), and phenotype 4 (ANOV + PCO). Anti-Müllerian hormone (AMH) was suggested to play a pathophysiologic and diagnostic role in this syndrome. The aim of this study was to compare AMH levels among the different phenotypes in relation to clinical, endocrine, and metabolic features. We enrolled 117 women with PCOS (body mass index: 25.89 ± 6.20 kg/m(2), age range: 18-37 years) and 24 controls. Anthropometric characteristics, hirsutism score, ultrasound ovarian features, and hormonal parameters, including AMH, were evaluated. Each participant also underwent an oral glucose tolerance test and an euglycemic-hyperinsulinemic clamp. The prevalence of phenotypes 1 to 4 was 62.4%, 8.6%, 11.1%, and 17.9%, respectively. Body mass index and insulin resistance indexes were similar among the groups. Phenotype 1 showed the highest luteinizing hormone, androgens levels, ovarian volume, and AMH concentrations (9.27 ± 8.17 ng/mL,P< .05) versus phenotype 2 and controls. Phenotype 2 women were hirsute, showed an intermediate free androgen index value, low ovarian volume, and low AMH levels (4.05 ± 4.12 ng/mL). Phenotype 3 showed an intermediate state of HA and slightly augmented AMH levels (5.87 ± 4.35 ng/mL). The clinical and endocrine characteristics of phenotype 4 resembled those of controls, except for higher ovarian volume and AMH levels (7.62 ± 3.85 ng/mL;P< .05). Our results highlight the heterogeneity of the association between increased AMH levels, menstrual dysfunction, and HA in the different PCOS phenotypes, thus offering a key to an understanding of the current controversy on the value of AMH measurement in PCOS. PMID:26718304

  1. Deciphering the Galaxy Guppy phenotype

    Directory of Open Access Journals (Sweden)

    Philip Shaddock

    2011-01-01

    Full Text Available Animal breeding hobbyists have been useful to science because they identify and isolate colorcoat mutations that geneticists can in turn use in their studies of the development and differentiation ofcolor cells. This paper discusses a very interesting color mutant, the Japanese Galaxy, tracing its creationfrom back to a self-educated genetics hobbyist, Hoskiki Tsutsui. The paper discusses a constituent genepreviously studied by Dr. Violet Phang, the snakeskin gene (the linked body and fin genes Ssb and Sst.And it discusses a gene previously unknown to science, the Schimmelpfennig Platinum gene (Sc.Through crossing experiments, the author determines that the combination of these two genes producesan intermediate phenotype, the Medusa. Incorporating the Grass (Gr, another gene unknown to sciencegene into the Medusa through a crossover produces the Galaxy phenotype. Microscope studies of thesnakeskin pattern in Galaxies and snakeskins reveals some parallels with similar studies made of theZebrafish Danio.

  2. Phenotypic variability in Meesmann's dystrophy

    DEFF Research Database (Denmark)

    Ehlers, Niels; Hjortdal, Jesper; Nielsen, Kim;

    2008-01-01

    symptoms often include blurred vision and ocular irritation. Typical cases may be entirely free of complaints. Intermittent pain episodes, such as occur in recurrent erosion syndrome, are not the rule. Genetic sequencing indicated a familial relationship with the originally described Meesmann family......'s dystrophy occurs worldwide. The largest family described is the original German one, now supplemented with a Danish branch. Despite the presence of an identical genetic defect, the clinical phenotype varies. This suggests that non-KRT12-related mechanisms are responsible for the variation.......PURPOSE: To describe the phenotypic variability in Meesmann's microcystic dystrophy of the corneal epithelium based on a review of the literature and the presentation of a Danish family. METHODS: We carried out a clinical examination of the family and genetic sequencing of DNA. RESULTS: Subjective...

  3. Phenotypic expression in mucopolysaccharidosis VII.

    OpenAIRE

    Bernsen, P L; Wevers, R. A.; Gabreëls, F J; Lamers, K J; Sonnen, A E; Stekhoven, J H

    1987-01-01

    beta-glucuronidase deficiency is an extremely rare disorder which is known to have a considerable phenotypic variation. A survey of the clinical findings in 19 previously reported patients with mucopolysaccharidosis VII is presented together with the results of clinical and biochemical studies in two further patients. Because a similar clinical picture is present in a heterozygotic sister it is doubted whether all signs and symptoms can be attributed to the beta-glucuronidase deficiency. The ...

  4. [Plasticity of the cellular phenotype].

    Science.gov (United States)

    Chneiweiss, Hervé

    2011-01-01

    The tragical consequences of the Hiroshima and Nagasaki atomic bombs in 1945 were to lead to the discovery of hematopoietic stem cells and their phenotypic plasticity, in response to environmental factors. These concepts were much later extended to the founding cells of other tissues. In the following collection of articles, the mechanisms underlying this plasticity, at the frontiers of developmental biology and oncology, are illustrated in the case of various cell types of neural origin and of some tumours. PMID:21501574

  5. Wine Expertise Predicts Taste Phenotype

    OpenAIRE

    Hayes, John E.; Pickering, Gary J

    2012-01-01

    Taste phenotypes have long been studied in relation to alcohol intake, dependence, and family history, with contradictory findings. However, on balance – with appropriate caveats about populations tested, outcomes measured and psychophysical methods used – an association between variation in taste responsiveness and some alcohol behaviors is supported. Recent work suggests super-tasting (operationalized via propylthiouracil (PROP) bitterness) not only associates with heightened response but a...

  6. Statistical models for trisomic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Lamb, N.E.; Sherman, S.L.; Feingold, E. [Emory Univ., Atlanta, GA (United States)

    1996-01-01

    Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known. 21 refs., 8 figs., 1 tab.

  7. Genetic background of phenotypic variation

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A noteworthy feature of the living world is its bewildering variability. A key issue in several biological disciplines is the achievement of an understanding of the hereditary basis of this variability. Two opposing, but not necessarily irreconcilable conceptions attempt to explain the underlying mechanism. The gene function paradigm postulates that phenotypic variance is generated by the polymorphism in the coding sequences of genes. However, comparisons of a great number of homologous gene and protein sequences have revealed that they predominantly remained functionally conserved even across distantly related phylogenic taxa. Alternatively, the gene regulation paradigm assumes that differences in the cis-regulatory region of genes do account for phenotype variation within species. An extension of this latter concept is that phenotypic variability is generated by the polyrnorphism in the overall gene expression profiles of gene networks.In other words, the activity of a particular gene is a system property determined both by the cis-regulatory sequences of the given genes and by the other genes of a gene network, whose expressions vary among individuals, too. Novel proponents of gene function paradigm claim that functional genetic variance within the coding sequences of regulatory genes is critical for the generation of morphological polymorphism. Note, however, that these developmental genes play direct regulatory roles in the control of gene expression.

  8. 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

  9. Multivariate Analysis of Genotype-Phenotype Association.

    Science.gov (United States)

    Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

    2016-04-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map

  10. Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes

    DEFF Research Database (Denmark)

    Mumm, Hanne; Jensen, Dorte Møller; Sørensen, Jens Aage;

    2015-01-01

    characteristics and obstetric outcomes were collected in patients with PCOS and HA and controls. In PCOS and HA, total and free testosterone, sex hormone binding globulin, and hemoglobin A1c were measured outside pregnancy. During pregnancy, oral glucose tolerance tests were performed in 39 patients and 123....... RESULTS: The incidence of adverse obstetric outcomes and anthropometric measures among the newborns were comparable between different phenotypes of PCOS and patients with HA. During oral glucose tolerance test, patients had higher risk of gestational diabetes mellitus compared to controls; odds ratio (95......% confidence interval) 3.3 (1.5-6.9) after adjustment for age, parity, and body mass index (p = 0.002). The incidence of other adverse obstetric outcomes was similar in patients vs. controls. CONCLUSIONS: Obstetric outcomes were comparable between different PCOS phenotypes. This article is protected by...

  11. 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...

  12. Salt Tolerance in Soybean

    Institute of Scientific and Technical Information of China (English)

    Tsui-Hung Phang; Guihua Shao; Hon-Ming Lam

    2008-01-01

    Soybean is an Important cash crop and its productivity is significantly hampered by salt stress. High salt Imposes negative impacts on growth, nodulation, agronomy traits, seed quality and quantity, and thus reduces the yield of soybean. To cope with salt stress, soybean has developed several tolerance mechanisms, including: (I) maintenance of ion homeostasis; (ii) adjustment in response to osmotic stress; (iii) restoration of osmotic balance; and (iv) other metabolic and structural adaptations. The regulatory network for abiotic stress responses in higher plants has been studied extensively in model plants such as Arabidopsis thaliana. Some homologous components involved in salt stress responses have been identified in soybean. In this review, we tried to integrate the relevant works on soybean and proposes a working model to descdbe Its salt stress responses at the molecular level.

  13. Expressing the sweet potato orange gene in transgenic potato improves drought tolerance and marketable tuber production.

    Science.gov (United States)

    Cho, Kwang-Soo; Han, Eun-Heui; Kwak, Sang-Soo; Cho, Ji-Hong; Im, Ju-Seong; Hong, Su-Young; Sohn, Hwang-Bae; Kim, Yun-Hee; Lee, Shin-Woo

    2016-01-01

    Potato (Solanum tuberosum L.) is generally considered to be sensitive to drought stress. Even short periods of water shortage can result in reduced tuber production and quality. We previously reported that transgenic potato plants expressing the sweet potato orange gene (IbOr) under the control of the stress-inducible SWPA2 promoter (referred to as SOR plants) showed increased tolerance to methyl viologen-mediated oxidative stress and high salinity, along with increased carotenoid contents. In this study, in an effort to improve the productivity and environmental stress tolerance of potato, we subjected transgenic potato plants expressing IbOr to water-deficient conditions in the greenhouse. The SOR plants exhibited increased tolerance to drought stress under greenhouse conditions. IbOr expression was associated with slightly negative phenotypes, including reduced tuber production. Controlling IbOr expression imparted the same degree of drought tolerance while ameliorating these negative phenotypic effects, leading to levels of tuber production similar to or better than those of wild-type plants under drought stress conditions. In particular, under drought stress, drought tolerance and the production of marketable tubers (over 80g) were improved in transgenic plants compared with non-transgenic plants. These results suggest that expressing the IbOr transgene can lead to significant gains in drought tolerance and tuber production in potato, thereby improving these agronomically important traits. PMID:27212605

  14. Natural variation in cold tolerance in the nematode Pristionchus pacificus: the role of genotype and environment

    Directory of Open Access Journals (Sweden)

    Angela McGaughran

    2014-08-01

    Full Text Available Low temperature is a primary determinant of growth and survival among organisms and almost all animals need to withstand temperature fluctuations in their surroundings. We used the hermaphroditic nematode Pristionchus pacificus to examine variation in cold tolerance in samples collected from 18 widespread locations. Samples were challenged by exposure to both direct and gradual low temperature after culture in the laboratory at 20°C. A short-term acclimation treatment was also applied to assess cold tolerance following a pre-exposure cold treatment. Finally, genotype-by-environment (G × E analysis was performed on a subset of samples cultured at two additional temperatures (15°C and 25°C. P. pacificus displayed a high degree of natural variation in cold tolerance, corresponding to the presence of three distinct phenotypic classes among samples: cold tolerant, non-cold tolerant, cold tolerant plastic. Survival of gradual cold exposure was significantly higher than survival of direct exposure to low temperature and a cold exposure pre-treatment significantly enhanced cold tolerance in some samples. By focusing on a sub-set of well-sampled locations from tropical La Réunion Island, we found evidence of significant effects of genotype and environment on cold tolerance, and we also showed that, within the different Réunion locations sampled, all three phenotypic classes are generally well represented. Taken together, our results show that P. pacificus exhibits a highly plastic tolerance to cold exposure that may be partly driven by differential trait sensitivity in diverse environments.

  15. Legal Quality, Inequality, and Tolerance

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    Previous findings suggest that income inequality leads to lower legal quality. This paper argues that voters' tolerance of inequality exerts an additional influence. Empirical findings suggest that inequality leads to lower legal quality due to its effect on trust while the tolerance of inequality...

  16. Legal Quality, Inequality, and Tolerance

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2004-01-01

    Previous findings suggest that income inequality leads to lower legal quality. This paper argues that voters' tolerance of inequality exerts an additional influence. Empirical findings suggest that inequality leads to lower legal quality due to its effect on trust while the tolerance of inequality...

  17. Efficient α, β-motif finder for identification of phenotype-related functional modules

    Directory of Open Access Journals (Sweden)

    Schmidt Matthew C

    2011-11-01

    Full Text Available Abstract Background Microbial communities in their natural environments exhibit phenotypes that can directly cause particular diseases, convert biomass or wastewater to energy, or degrade various environmental contaminants. Understanding how these communities realize specific phenotypic traits (e.g., carbon fixation, hydrogen production is critical for addressing health, bioremediation, or bioenergy problems. Results In this paper, we describe a graph-theoretical method for in silico prediction of the cellular subsystems that are related to the expression of a target phenotype. The proposed (α, β-motif finder approach allows for identification of these phenotype-related subsystems that, in addition to metabolic subsystems, could include their regulators, sensors, transporters, and even uncharacterized proteins. By comparing dozens of genome-scale networks of functionally associated proteins, our method efficiently identifies those statistically significant functional modules that are in at least α networks of phenotype-expressing organisms but appear in no more than β networks of organisms that do not exhibit the target phenotype. It has been shown via various experiments that the enumerated modules are indeed related to phenotype-expression when tested with different target phenotypes like hydrogen production, motility, aerobic respiration, and acid-tolerance. Conclusion Thus, we have proposed a methodology that can identify potential statistically significant phenotype-related functional modules. The functional module is modeled as an (α, β-clique, where α and β are two criteria introduced in this work. We also propose a novel network model, called the two-typed, divided network. The new network model and the criteria make the problem tractable even while very large networks are being compared. The code can be downloaded from http://www.freescience.org/cs/ABClique/

  18. The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy

    OpenAIRE

    Guang Yang; Qingli Cheng; Sheng Liu; Jiahui Zhao

    2015-01-01

    The aim of our study was to investigate the role of bone marrow cells in the phenotypic changes that occur in diabetic nephropathy. Bone marrow cells were obtained from either streptozotocin-induced diabetic or untreated control C3H/He mice and transplanted into control C3H/He mice. Eight weeks after bone marrow cell transplantation, renal morphologic changes and clinical parameters of diabetic nephropathy, including the urine albumin/creatinine ratio and glucose tolerance, were measured in v...

  19. Statistical models in agriculture: biometrical methods for evaluating phenotypic stability in plant breeding

    OpenAIRE

    Daniel Furtado Ferreira; Clarice Garcia Borges Demétrio; Bryan Frederick John Manly ,Roland Vencovsky; Amauri de Almeida Machado; Roland Vencovsky

    2006-01-01

    This paper reviews the main concepts of several methods of phenotypic stability analysis and points out their advantages and limitations. It was concluded that the simple linear regression method of Eberhart & Russel (1966) and the bi?segmented regression method of Silva & Barreto (1985) have only historical importance nowadays. Moreover, based on factors discussed in the paper, it is recommended that the regression models of Toler & Burrows (1998) and the Additive Main effects and Multiplica...

  20. Molecular polymorphism distribution in phenotypically distinct populations of wine yeast strains

    OpenAIRE

    Nadal, Dolors; Colomer, Bruno; Piña, Benjamín

    1996-01-01

    Electrophoretic karyotyping and mitochondrial DNA restriction analysis were used to analyze natural yeast populations from fermenting musts in El Penedès, Spain. Both analyses revealed a considerable degree of polymorphism, indicating heterogeneous natural populations. By specifically designed genetic selection protocols, strains showing potentially interesting phenotypes, such as high tolerance to ethanol and temperature or the ability to grow and to ferment in wine-water-sugar mixtures, wer...

  1. 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.

  2. Knowledge-based analysis of phenotypes

    KAUST Repository

    Hoendorf, Robert

    2016-01-27

    Phenotypes are the observable characteristics of an organism, and they are widely recorded in biology and medicine. To facilitate data integration, ontologies that formally describe phenotypes are being developed in several domains. I will describe a formal framework to describe phenotypes. A formalized theory of phenotypes is not only useful for domain analysis, but can also be applied to assist in the diagnosis of rare genetic diseases, and I will show how our results on the ontology of phenotypes is now applied in biomedical research.

  3. EHD1 functions in endosomal recycling and confers salt tolerance.

    Directory of Open Access Journals (Sweden)

    Maya Bar

    Full Text Available Endocytosis is a crucial process in all eukaryotic organisms including plants. We have previously shown that two Arabidopsis proteins, AtEHD1 and AtEHD2, are involved in endocytosis in plant systems. Knock-down of EHD1 was shown to have a delayed recycling phenotype in mammalians. There are many works in mammalian systems detailing the importance of the various domains in EHDs but, to date, the domains of plant EHD1 that are required for its activity have not been characterized. In this work we demonstrate that knock-down of EHD1 causes a delayed recycling phenotype and reduces Brefeldin A sensitivity in Arabidopsis seedlings. The EH domain of EHD1 was found to be crucial for the localization of EHD1 to endosomal structures. Mutant EHD1 lacking the EH domain did not localize to endosomal structures and showed a phenotype similar to that of EHD1 knock-down seedlings. Mutants lacking the coiled-coil domain, however, showed a phenotype similar to wild-type or EHD1 overexpression seedlings. Salinity stress is a major problem in current agriculture. Microarray data demonstrated that salinity stress enhances the expression of EHD1, and this was confirmed by semi quantitative RT-PCR. We demonstrate herein that transgenic plants over expressing EHD1 possess enhanced tolerance to salt stress, a property which also requires an intact EH domain.

  4. Quantitative Trait Loci for Mercury Tolerance in Rice Seedlings

    Institute of Scientific and Technical Information of China (English)

    WANG Chong-qing; WANG Tao; MU Ping; LI Zi-chao; YANG Ling

    2013-01-01

    Mercury (Hg) is one of the most toxic heavy metals to living organisms and its conspicuous effect is the inhibition of root growth.However,little is known about the molecular genetic basis for root growth under excess Hg2+ stress.To map quantitative trait loci (QTLs) in rice for Hg2+ tolerance,a population of 120 recombinant inbred lines derived from a cross between two japonica cultivars Yuefu and IRAT109 was grown in 0.5 mmol/L CaCl2 solution.Relative root length (RRL),percentage of the seminal root length in +HgCl2 to -HgCl2,was used for assessing Hg2+ tolerance.In a dose-response experiment,Yuefu had a higher RRL than IRAT109 and showed the most significant difference at the Hg2+ concentration of 1.5 μmol/L.Three putative QTLs for RRL were detected on chromosomes 1,2 and 5,and totally explained about 35.7% of the phenotypic variance in Hg2+ tolerance.The identified QTLs for RRL might be useful for improving Hg2+ tolerance of rice by molecular marker-assisted selection.

  5. A CAD MODEL FOR FUZZY CONCURRENT TOLERANCE

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Research situation of concurrent tolerance design has been analyzed. As fuzzy factors are objective and unavoidable in concurrent tolerance design, fuzzy optimization theory is applied in the design. A new mathematical model of concurrent tolerance design is constructed.

  6. Hemogoblin phenotypes in Murgese horse

    OpenAIRE

    Carmela Bottiglieri; Rosario Rullo; Aldo Di Luccia; Elisa Pieragostini

    2010-01-01

    In this note we describe two new equine hemoglobin phenotypes found during a survey of the Murgese horse, a rare  Apulian native breed, among whose ancestors the Arabian surely plays an important role. To date we have analysed about  300 individual hemolysates by different chromatographic analyses (PAGIF, IPG, CMC). The results pointed out two unusu-  al patterns where the ratio of the α24Phe60Gln band to the α24Phe60Lys band was 93:7 and 70:30 rather than 60:40&nbs...

  7. Phenotypic MicroRNA Microarrays

    OpenAIRE

    Veronica Soloveva; Michel Liuzzi; Jin Yeop Kim; Hi Chul Kim; Jin Yeong Heo; Yong-Jun Kwon

    2013-01-01

    Microarray technology has become a very popular approach in cases where multiple experiments need to be conducted repeatedly or done with a variety of samples. In our lab, we are applying our high density spots microarray approach to microscopy visualization of the effects of transiently introduced siRNA or cDNA on cellular morphology or phenotype. In this publication, we are discussing the possibility of using this micro-scale high throughput process to study the role of microRNAs in the bio...

  8. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes

    Science.gov (United States)

    Qie, Yaqing; Yuan, Hengfeng; von Roemeling, Christina A.; Chen, Yuanxin; Liu, Xiujie; Shih, Kevin D.; Knight, Joshua A.; Tun, Han W.; Wharen, Robert E.; Jiang, Wen; Kim, Betty Y. S.

    2016-05-01

    Nanomedicine is a burgeoning industry but an understanding of the interaction of nanomaterials with the immune system is critical for clinical translation. Macrophages play a fundamental role in the immune system by engulfing foreign particulates such as nanoparticles. When activated, macrophages form distinct phenotypic populations with unique immune functions, however the mechanism by which these polarized macrophages react to nanoparticles is unclear. Furthermore, strategies to selectively evade activated macrophage subpopulations are lacking. Here we demonstrate that stimulated macrophages possess higher phagocytic activities and that classically activated (M1) macrophages exhibit greater phagocytic capacity than alternatively activated (M2) macrophages. We show that modification of nanoparticles with polyethylene-glycol results in decreased clearance by all macrophage phenotypes, but importantly, coating nanoparticles with CD47 preferentially lowers phagocytic activity by the M1 phenotype. These results suggest that bio-inspired nanoparticle surface design may enable evasion of specific components of the immune system and provide a rational approach for developing immune tolerant nanomedicines.

  9. Germplasm Innovation of Heat Tolerance in Rice for Irrigated Lowland Conditions in the Philippines

    Institute of Scientific and Technical Information of China (English)

    Norvie L.MANIGBAS; Leslie Angela F.LAMBIO; Luvina B.MADRID; Corazon C.CARDENAS

    2014-01-01

    Heat-tolerant varieties, such as N22 and Dular, which were used in this study, usually have low yield potential and undesirable plant characteristics but combining them with high yielding and improved rice varieties, new heat-tolerant rice genotypes with high yield potential can be achieved. In this study, phenotyping and selecting desirable materials from various crosses were performed under high temperature conditions during the reproductive stage. Screening was performed in the field and glasshouse to select individuals with heat tolerance and high yield potential. Several advanced breeding lines from Gayabyeo/N22 cross produced desirable individuals with heat tolerance, resistance to pests and diseases, and high yield potential. The genetic variation in percent sterility among the selected backcross populations grown in high temperature environments showed that large number of plants can be identified and selected with lower percent sterility.

  10. 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

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

    Science.gov (United States)

    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

  12. 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

  13. 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

  14. The culture of tolerance in diverse societies: Reasonable toleration

    OpenAIRE

    McKinnon, Catriona; Castiglione, Dario

    2003-01-01

    The idea of toleration as the appropriate response to difference has been central to liberal thought since Locke. Although the subject has been widely and variously explored, there has been reluctance to acknowledge the new meaning that current debates on toleration have when compared with those at its origins in the early modern period and with subsequent discussions about pluralism and freedom of expression. This collection starts from a clear recognition of the new terms of the debate. It ...

  15. Photoinhibition and drought in Mediterranean woody saplings: scaling effects and interactions in sun and shade phenotypes.

    Science.gov (United States)

    Valladares, Fernando; Dobarro, Iker; Sánchez-Gómez, David; Pearcy, Robert W

    2005-01-01

    Interacting effects of high light and drought on the performance of sun and shade phenotypes were experimentally undertaken following survival, chlorophyll fluorescence and gas exchange in 2-year-old saplings of four Mediterranean trees (Quercus ilex and Q. coccifera as water-saving species, and Pistacia lentiscus and P. terebinthus as water-spending species). Half of the saplings were grown in full sunlight and the other half in the shade (6% sunlight). Half of each combination of species-phenotype was exposed to high light during a simulated late-summer drought. Light absorptance and gas exchange were scaled up to the whole plant with the 3-D geometrical model, Y-Plant. Quercus species were more plastic and tolerated high light and water stress better than Pistacia species, surviving longer and in drier soils, and exhibiting a less pronounced photoinhibition. There was no evidence of disadvantage for shade phenotypes under high light with increasing drought. By contrast, shade phenotypes survived longer despite larger initial decreases in photochemical efficiency and higher sensitivity to drought than sun phenotypes. The enhanced control of transpiration during drought in water-saving versus water-spending species (and also in shade versus sun phenotypes in three out of the four species) allowed extended survival. Photoinhibition reduced whole crown carbon gain in high light by c. 3% and affected significantly more the shaded leaves of a given plant (reducing their carbon gain by up to 7%) than those exposed to direct sunlight. Despite this apparently minor impact, whole plant carbon gain reduction by photoinhibition negatively correlated with survival and drought tolerance. The implications for succession and forest regeneration in arid environments, particularly under a global change scenario, are discussed. PMID:15569705

  16. Antibiotic tolerance and microbial biofilms

    DEFF Research Database (Denmark)

    Folkesson, Anders

    Increased tolerance to antimicrobial agents is thought to be an important feature of microbes growing in biofilms. We study the dynamics of antibiotic action within hydrodynamic flow chamber biofilms of Escherichia coli and Pseudomonas aeruginosa using isogenic mutants and fluorescent gene...... expression reporters and we address the question of how biofilm organization affects antibiotic susceptibility. The dynamics of microbial killing is monitored by viable count determination, and confocal laser microscopy. Our work shows that the apparent increased antibiotic tolerance is due to the formation...... of antibiotic tolerant subpopulations within the biofilm. The formation of these subpopulations is highly variable and dependent on the antibiotic used, the biofilm structural organization and the induction of specific tolerance mechanisms....

  17. Accident tolerant fuel analysis

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Curtis [Idaho National Laboratory; Chichester, Heather [Idaho National Laboratory; Johns, Jesse [Texas A& M University; Teague, Melissa [Idaho National Laboratory; Tonks, Michael Idaho National Laboratory; Youngblood, Robert [Idaho National Laboratory

    2014-09-01

    Safety is central to the design, licensing, operation, and economics of Nuclear Power Plants (NPPs). Consequently, the ability to better characterize and quantify safety margin holds the key to improved decision making about light water reactor design, operation, and plant life extension. A systematic approach to characterization of safety margins and the subsequent margins management options represents a vital input to the licensee and regulatory analysis and decision making that will be involved. The purpose of the Risk Informed Safety Margin Characterization (RISMC) Pathway research and development (R&D) is to support plant decisions for risk-informed margins management by improving economics and reliability, and sustaining safety, of current NPPs. Goals of the RISMC Pathway are twofold: (1) Develop and demonstrate a risk-assessment method coupled to safety margin quantification that can be used by NPP decision makers as part of their margin recovery strategies. (2) Create an advanced ''RISMC toolkit'' that enables more accurate representation of NPP safety margin. In order to carry out the R&D needed for the Pathway, the Idaho National Laboratory is performing a series of case studies that will explore methods- and tools-development issues, in addition to being of current interest in their own right. One such study is a comparative analysis of safety margins of plants using different fuel cladding types: specifically, a comparison between current-technology Zircaloy cladding and a notional ''accident-tolerant'' (e.g., SiC-based) cladding. The present report begins the process of applying capabilities that are still under development to the problem of assessing new fuel designs. The approach and lessons learned from this case study will be included in future Technical Basis Guides produced by the RISMC Pathway. These guides will be the mechanism for developing the specifications for RISMC tools and for defining how plant

  18. Effect of sequential heat and cold shocks on nuclear phenotypes of the blood-sucking insect, Panstrongylus megistus (Burmeister) (Hemiptera, Reduviidae)

    OpenAIRE

    Garcia Simone L; Pacheco Raquel M; Rodrigues Vera LCC; Mello Maria Luiza S.

    2002-01-01

    Thermal shocks induce changes in the nuclear phenotypes that correspond to survival (heterochromatin decondensation, nuclear fusion) or death (apoptosis, necrosis) responses in the Malpighian tubules of Panstrongylus megistus. Since thermal tolerance increased survival and molting rate in this species following sequential shocks, we investigated whether changes in nuclear phenotypes accompanied the insect survival response to sequential thermal shocks. Fifth instar nymphs were subjected to a ...

  19. Desiccation tolerance of somatic embryoids.

    OpenAIRE

    Tetteroo, F.A.A.

    1996-01-01

    This thesis describes the research performed on the subject "Desiccation tolerance in somatic embryoids". Somatic embryoids are bipolar structures formed in tissue culture, with both a shoot and a root apex, which resemble very much zygotic embryos found in seeds. Through simultaneous development of root and shoot, these embryoids can grow out into complete plantlets.In Chapter 2 we describe an optimized method to produce completely desiccation tolerant carrot ( Daucus carota ) embryoids. Usi...

  20. Hemogoblin phenotypes in Murgese horse

    Directory of Open Access Journals (Sweden)

    Carmela Bottiglieri

    2010-01-01

    Full Text Available In this note we describe two new equine hemoglobin phenotypes found during a survey of the Murgese horse, a rare  Apulian native breed, among whose ancestors the Arabian surely plays an important role. To date we have analysed about  300 individual hemolysates by different chromatographic analyses (PAGIF, IPG, CMC. The results pointed out two unusu-  al patterns where the ratio of the α24Phe60Gln band to the α24Phe60Lys band was 93:7 and 70:30 rather than 60:40  which would have been expected of BII homozygote. Given that the three horses exhibiting the unusual patterns shared  a common ancestor and that none of the possible combinations of the known haplotypes can account for 7-8%  α24Phe60Lys, reasonably a triplicated arrangement has to be postulated. 

  1. Phenotyping for drought adaptation in wheat using physiological traits

    Directory of Open Access Journals (Sweden)

    Philippe eMonneveux

    2012-11-01

    Full Text Available Wheat (Triticum spp is one of the first domesticated food crops. It represents the first source of calories (after rice and an important source of proteins in developing countries. As a result of the Green Revolution, wheat yield sharply increased due to the use of improved varieties, irrigation, pesticides and fertilizers. The rate of increase in world wheat production however slowed after 1980, except in China, India and Pakistan. Being adapted to a wide range of moisture conditions, wheat is grown on more land area worldwide than any other crop, including in drought prone areas. In these marginal rain-fed environments where at least 60m ha of wheat is grown, amount and distribution of rainfall are the predominant factors influencing yield variability. Intensive work has been carried out in the area of drought adaptation over the last decades. Breeding strategies for drought tolerance improvement include: definition of the target environment, choice and characterisation of the testing environment, water stress management and characterization, and use of phenotyping traits with high heritability. The use of integrative traits, facilitated by the development and application of new technologies (thermal imaging, spectral reflectance, stable isotopes is facilitating high throughput phenotyping and indirect selection, consequently favoring yield improvement in drought prone environments.

  2. Systems Biology for Mapping Genotype-Phenotype Relations in Yeast

    KAUST Repository

    Nielsen, Jens

    2016-01-25

    The yeast Saccharomyces cerevisiae is widely used for production of fuels, chemicals, pharmaceuticals and materials. Through metabolic engineering of this yeast a number of novel new industrial processes have been developed over the last 10 years. Besides its wide industrial use, S. cerevisiae serves as an eukaryal model organism, and many systems biology tools have therefore been developed for this organism. Among these genome-scale metabolic models have shown to be most successful as they easy integrate with omics data and at the same time have been shown to have excellent predictive power. Despite our extensive knowledge of yeast metabolism and its regulation we are still facing challenges when we want to engineer complex traits, such as improved tolerance to toxic metabolites like butanol and elevated temperatures or when we want to engineer the highly complex protein secretory pathway. In this presentation it will be demonstrated how we can combine directed evolution with systems biology analysis to identify novel targets for rational design-build-test of yeast strains that have improved phenotypic properties. In this lecture an overview of systems biology of yeast will be presented together with examples of how genome-scale metabolic modeling can be used for prediction of cellular growth at different conditions. Examples will also be given on how adaptive laboratory evolution can be used for identifying targets for improving tolerance towards butanol, increased temperature and low pH and for improving secretion of heterologous proteins.

  3. Clinical Asthma Phenotypes and Therapeutic Responses

    OpenAIRE

    Zedan, M.; Attia, G.; Zedan, M. M.; Osman, A; Abo-Elkheir, N.; Maysara, N.; Barakat, T.; Gamil, N.

    2013-01-01

    Asthma is a heterogeneous disease that means not all asthmatics respond to the same treatment. We hypothesize an approach to characterize asthma phenotypes based on symptomatology (shortness of breath (SOB), cough, and wheezy phenotypes) in correlation with airway inflammatory biomarkers and FEV1. We aimed to detect whether those clinical phenotypes have an impact on the response to asthma medications. Two hundred three asthmatic children were allocated randomly to receive either montelukast ...

  4. Latent phenotypes pervade gene regulatory circuits.

    OpenAIRE

    Payne, Joshua L.; Wagner, Andreas

    2014-01-01

    BACKGROUND Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. RESULTS Here, we study a space of more than sixteen million three-gene model regulatory circ...

  5. Latent phenotypes pervade gene regulatory circuits

    OpenAIRE

    Payne, Joshua L.; Wagner, Andreas

    2014-01-01

    Background Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. Results Here, we study a space of more than sixteen million three-gene model regulatory circuit...

  6. Phenotype Information Retrieval for Existing GWAS Studies

    OpenAIRE

    Alipanah, Neda; Lin, Ko-Wei; Venkatesh, Vinay; Farzaneh, Seena; Kim, Hyeon-eui

    2013-01-01

    The database of Genotypes and Phenotypes (dbGaP) is archiving the results of different Genome Wide Association Studies (GWAS). dbGaP has a multitude of phenotype variables, but they are not harmonized across studies. We proposed a method to standardize phenotype variables by classifying similar variables based on semantic distances. We first extracted variables description, enriched them using domain knowledge, and computed the distances among them. We used clustering techniques to classify t...

  7. Phenotypes and Survival of Hatchling Lizards

    OpenAIRE

    Warner, Daniel Augustus

    2001-01-01

    The phenotypes of hatchling reptiles are influenced by the environmental conditions that embryos experience during incubation, by yolk invested into the egg, and by the genetic contributions of the parents. Phenotypic traits are influenced by these factors in ways that potentially affect the fitness of hatchlings. The physical conditions that embryos experience within the nest affects development, hatching success, and hatchling phenotypes. Thus, the nest site that a female selects can inf...

  8. Integrated genomics, physiology and breeding approaches for improving drought tolerance in crops.

    Science.gov (United States)

    Mir, Reyazul Rouf; Zaman-Allah, Mainassara; Sreenivasulu, Nese; Trethowan, Richard; Varshney, Rajeev K

    2012-08-01

    Drought is one of the most serious production constraint for world agriculture and is projected to worsen with anticipated climate change. Inter-disciplinary scientists have been trying to understand and dissect the mechanisms of plant tolerance to drought stress using a variety of approaches; however, success has been limited. Modern genomics and genetic approaches coupled with advances in precise phenotyping and breeding methodologies are expected to more effectively unravel the genes and metabolic pathways that confer drought tolerance in crops. This article discusses the most recent advances in plant physiology for precision phenotyping of drought response, a vital step before implementing the genetic and molecular-physiological strategies to unravel the complex multilayered drought tolerance mechanism and further exploration using molecular breeding approaches for crop improvement. Emphasis has been given to molecular dissection of drought tolerance by QTL or gene discovery through linkage and association mapping, QTL cloning, candidate gene identification, transcriptomics and functional genomics. Molecular breeding approaches such as marker-assisted backcrossing, marker-assisted recurrent selection and genome-wide selection have been suggested to be integrated in crop improvement strategies to develop drought-tolerant cultivars that will enhance food security in the context of a changing and more variable climate. PMID:22696006

  9. The Metabolic Basis of Pollen Thermo-Tolerance: Perspectives for Breeding

    Directory of Open Access Journals (Sweden)

    Marine J. Paupière

    2014-09-01

    Full Text Available Crop production is highly sensitive to elevated temperatures. A rise of a few degrees above the optimum growing temperature can lead to a dramatic yield loss. A predicted increase of 1–3 degrees in the twenty first century urges breeders to develop thermo-tolerant crops which are tolerant to high temperatures. Breeding for thermo-tolerance is a challenge due to the low heritability of this trait. A better understanding of heat stress tolerance and the development of reliable methods to phenotype thermo-tolerance are key factors for a successful breeding approach. Plant reproduction is the most temperature-sensitive process in the plant life cycle. More precisely, pollen quality is strongly affected by heat stress conditions. High temperature leads to a decrease of pollen viability which is directly correlated with a loss of fruit production. The reduction in pollen viability is associated with changes in the level and composition of several (groups of metabolites, which play an important role in pollen development, for example by contributing to pollen nutrition or by providing protection to environmental stresses. This review aims to underline the importance of maintaining metabolite homeostasis during pollen development, in order to produce mature and fertile pollen under high temperature. The review will give an overview of the current state of the art on the role of various pollen metabolites in pollen homeostasis and thermo-tolerance. Their possible use as metabolic markers to assist breeding programs for plant thermo-tolerance will be discussed.

  10. Immunogenetic phenotypes in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Marla C Dubinsky; Kent Taylor; Stephan R Targan; Jerome I Rotter

    2006-01-01

    The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient

  11. Phenotypic heterogeneity of Streptococcus mutans in dentin.

    Science.gov (United States)

    Rupf, S; Hannig, M; Breitung, K; Schellenberger, W; Eschrich, K; Remmerbach, T; Kneist, S

    2008-12-01

    Information concerning phenotypic heterogeneity of Streptococcus mutans in carious dentin is sparse. Matrix-assisted laser-desorption/ionization-time-of-flight mass-spectrometry (MALDI-TOF-MS) facilitates the phenotypic differentiation of bacteria to the subspecies level. To verify a supposed influence of restorative treatment on the phenotypic heterogeneity of S. mutans, we isolated and compared a total of 222 S. mutans strains from dentin samples of 21 human deciduous molars during caries excavation (T(1)) and 8 wks (T(2)) after removal of the temporary restoration. Phenotypic heterogeneity was determined by MALDI-TOF-MS and hierarchical clustering. Thirty-six distinct S. mutans phenotypes could be identified. Although indistinguishable phenotypes were found in the same teeth at T(1) and T(2), as well as in different teeth of individual participants, the phenotypic heterogeneity increased significantly, from 1.4 phenotypes per S. mutans-positive dentin sample at T(1) to 2.2 phenotypes at T(2). We attribute this to an adaptation of S. mutans to the modified environment under the restoration following caries excavation. PMID:19029088

  12. Developing herbicide-tolerant crops from mutations

    International Nuclear Information System (INIS)

    Herbicide-tolerant crops in combination with their corresponding herbicides are able to control many weeds that cannot be or are less effectively controlled with other means. Commercial herbicide-tolerant crops developed from herbicide-tolerant mutants include imidazolinone-tolerant maize, rice, wheat, oilseed rape, sunflower, and lentil; sulfonylurea-tolerant soybean and sunflower; cyclohexanedione-tolerant maize; and triazine-tolerant oilseed rape. Most of the herbicide-tolerant mutants were developed through chemical mutagenesis followed by herbicide selection. Several herbicide-tolerant mutants were also discovered through direct herbicide selection of spontaneous mutations. All mutations used in commercial herbicide-tolerant crops are derived from a single nucleotide substitution of genes that encode enzymes or proteins targeted by herbicides. Imidazolinone-tolerant maize, rice, wheat, and oilseed rape have a gene variant encoding an altered acetohydoxyacid synthase (AHAS) with the S653N amino acid substitution. Additionally, imidazolinone-tolerant maize and oilseed rape have an AHAS with the W574L amino acid substitution. Imidazolinone-tolerant sunflower has been developed from the A205V AHAS gene mutation. In contrast, sulfonylurea-tolerant sunflower selected from a farm field has an AHAS enzyme variant with the P197L amino acid substitution. Similarly, sulfonylurea-tolerant soybean has a P197S AHAS gene mutation. Sulfonylurea-tolerant sunflower from seed mutagenesis and imidazolinone-tolerant lentil are also derived from AHAS gene mutations. Cyclohexanedione-tolerant maize has an altered acetyl-CoA carboxylase with the I1781L amino acid substitution. Triazine-tolerant oil seed rape possesses a psbA gene variant that encodes the D1 protein of photosynthesis with the S264G amino acid substitution. The alleles of all commercial herbicide-tolerant mutations are incompletely-dominant and not pleiotropic except for the triazine-tolerant mutation which is

  13. Evolutionary dynamics and highly optimized tolerance.

    Science.gov (United States)

    Zhou, Tong; Carlson, J M; Doyle, John

    2005-10-21

    We develop a numerical model of a lattice community based on Highly Optimized Tolerance (HOT), which relates the evolution of complexity to robustness tradeoffs in an uncertain environment. With the model, we explore scenarios for evolution and extinction which are abstractions of processes which are commonly discussed in biological and ecological case studies. These include the effects of different habitats on the phenotypic traits of the organisms, the effects of different mutation rates on adaptation, fitness, and diversity, and competition between generalists and specialists. The model exhibits a wide variety of microevolutionary and macroevolutionary phenomena which can arise in organisms which are subject to random mutation, and selection based on fitness evaluated in a specific environment. Generalists arise in uniform habitats, where different disturbances occur with equal frequency, while specialists arise when the relative frequency of different disturbances is skewed. Fast mutators are seen to play a primary role in adaptation, while slow mutators preserve well-adapted configurations. When uniform and skewed habitats are coupled through migration of the organisms, we observe a primitive form of punctuated equilibrium. Rare events in the skewed habitat lead to extinction of the specialists, whereupon generalists invade from the uniform habitat, adapt to their new surroundings, ultimately leading their progeny to become vulnerable to extinction in a subsequent rare disturbance. PMID:15904934

  14. Maintaining immunological tolerance with Foxp3

    Institute of Scientific and Technical Information of China (English)

    Lauren E Mays; Youhai H Chen

    2007-01-01

    Central tolerance in the thymus is the primary mechanism for deleting autoreactive T cells.Despite this,escape of self-reactive T lymphocytes into the periphery reveals the threat of autoimmunity.To compensate for its imperfection,the thymus also produces a naturally occurring subset ofFoxp3+CD4+CD25+regulatory T cells with suppressive function,capable of controlling autoreactive cells.Foxp3(forkhead box P3),the lineage-specific marker for this subset of cells,is crucial to their thymic development and peripheral function,and yet the transcriptional program driven by Foxp3 was until now largely undefined.Emerging evidence has provided insight into its role:from the ability of Foxp3 to cooperate with other transcription factors such as NFAT,to the genome-wide characterization of target genes directly bound and regulated by Foxp3.Here we discuss the discovery of naturally occurring regulatory T cells-their phenotype,development,maintenance,and function-largely as they are defined by the lineage-specific marker,Foxp3.

  15. Identification of quantitative trait loci for cadmium tolerance and accumulation in wheat

    DEFF Research Database (Denmark)

    Ci, Dunwei; Jiang, Dong; Li, Sishen;

    2012-01-01

    tolerance indexes (TI) were calculated for plants under Cd stress relative to control conditions. Cd concentrations in both root and shoot were determined and the amount of Cd accumulation and translocation calculated. The phenotypic variation of the above traits showed a continuous distribution pattern...... effects coming from Ch) while the remaining 12 QTLs were negative (with the additive effects contributed by Sh). No QTL were detected in the same region on the chromosomes of wheat. The results indicated that genetic mechanisms controlling the traits of Cd tolerance were independent from each other...

  16. Genetic dissection of drought tolerance in chickpea (Cicer arietinum L.)

    OpenAIRE

    Rajeev K. Varshney; Thudi, Mahendar; Nayak, Spurthi N.; Gaur, Pooran M.; Kashiwagi, Junichi; Krishnamurthy, Lakshmanan; Jaganathan, Deepa; Koppolu, Jahnavi; Bohra, Abhishek; Tripathi, Shailesh; Rathore, Abhishek; Aravind K. Jukanti; Jayalakshmi, Veera; Vemula, Anilkumar; Singh, S. J.

    2013-01-01

    Key message Analysis of phenotypic data for 20 drought tolerance traits in 1–7 seasons at 1–5 locations together with genetic mapping data for two mapping populations provided 9 QTL clusters of which one present on CaLG04 has a high potential to enhance drought tolerance in chickpea improvement. Abstract Chickpea (Cicer arietinum L.) is the second most important grain legume cultivated by resource poor farmers in the arid and semi-arid regions of the world. Drought is one of the major constra...

  17. Algorithms for worst-case tolerance optimization

    DEFF Research Database (Denmark)

    Schjær-Jacobsen, Hans; Madsen, Kaj

    1979-01-01

    New algorithms are presented for the solution of optimum tolerance assignment problems. The problems considered are defined mathematically as a worst-case problem (WCP), a fixed tolerance problem (FTP), and a variable tolerance problem (VTP). The basic optimization problem without tolerances is d...

  18. Mathematical model of cylindrical form tolerance

    Institute of Scientific and Technical Information of China (English)

    蔡敏; 杨将新; 吴昭同

    2004-01-01

    Tolerance is essential for integration of CAD and CAM. Unfortunately, the meaning of tolerances in the national standard is expressed in graphical and language forms and is not adaptable for expression, processing and data transferring with computers. How to interpret its semantics is becoming a focus of relevant studies. This work based on the mathematical definition of form tolerance in ANSI Y 14.5.1 M-1994, established the mathematical model of form tolerance for cylindrical feature. First, each tolerance in the national standard was established by vector equation. Then on the foundation of toler-ance's mathematical definition theory, each tolerance zone's mathematical model was established by inequality based on degrees of feature. At last the variance area of each tolerance zone is derived. This model can interpret the semantics of form tolerance exactly and completely.

  19. Can prenatal malaria exposure produce an immune tolerant phenotype? A prospective birth cohort study in Kenya.

    OpenAIRE

    Indu Malhotra; Arlene Dent; Peter Mungai; Alex Wamachi; Ouma, John H; Narum, David L.; Eric Muchiri; Tisch, Daniel J; King, Christopher L

    2009-01-01

    Editors' Summary Background Each year, Plasmodium falciparum, a mosquito-borne parasite, causes about 500 million cases of malaria and about one million people die as a result. Most of these deaths occur in young children in sub-Saharan Africa. Indeed, malaria accounts for a fifth of all childhood deaths in Africa, which makes it one of the most important childhood infectious diseases in this region. Very young children—those up to 6 months old—are relatively resistant to high-density parasit...

  20. Selection of tolerant rice germplasm through phenotypic and genotypic evaluation for germination under low temperatures

    Science.gov (United States)

    Low temperature germinability (LTG) is an important trait for stand establishment in the direct-seeding method of rice cultivation. In temperate growing regions, water temperature during sowing season is frequently below 15°C resulting in poor crop establishment. The objective of this study was to s...

  1. 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.

  2. Phenotypic robustness can increase phenotypic variability after non-genetic perturbations in gene regulatory circuits

    OpenAIRE

    Espinosa-Soto, C.; Martin, O. C.; Wagner, A

    2010-01-01

    Non-genetic perturbations, such as environmental change or developmental noise, can induce novel phenotypes. If an induced phenotype confers a fitness advantage, selection may promote its genetic stabilization. Non-genetic perturbations can thus initiate evolutionary innovation. Genetic variation that is not usually phenotypically visible may play an important role in this process. Populations under stabilizing selection on a phenotype that is robust to mutations can accumulate such variation...

  3. Developing Herbicide-Tolerant Crops from Mutations

    International Nuclear Information System (INIS)

    Several herbicide-tolerant crops have been developed and commercialized from herbicide-tolerant mutants obtained through chemical mutagenesis followed by herbicide selection or direct herbicide selection of spontaneous mutations. All mutations used in commercial herbicide-tolerant crops are derived from a single nucleotide substitution of genes that encode enzymes or proteins targeted by herbicides. The alleles of all commercial herbicide-tolerant mutations are incompletely-dominant except for the triazine-tolerant mutation. (author)

  4. Boolean Logic with Fault Tolerant Coding

    OpenAIRE

    Alagoz, B. Baykant

    2009-01-01

    Error detectable and error correctable coding in Hamming space was researched to discover possible fault tolerant coding constellations, which can implement Boolean logic with fault tolerant property. Basic logic operators of the Boolean algebra were developed to apply fault tolerant coding in the logic circuits. It was shown that application of three-bit fault tolerant codes have provided the digital system skill of auto-recovery without need for designing additional-fault tolerance mechanisms.

  5. 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

  6. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    NARCIS (Netherlands)

    Kohler, S.; Doelken, S.C.; Mungall, C.J.; Bauer, S.; Firth, H.V.; Bailleul-Forestier, I.; Black, G.C.M.; Brown, D.L.; Brudno, M.; Campbell, J.; FitzPatrick, D.R.; Eppig, J.T.; Jackson, A.P.; Freson, K.; Girdea, M.; Helbig, I.; Hurst, J.A.; Jahn, J.; Jackson, L.G.; Kelly, A.M.; Ledbetter, D.H.; Mansour, S.; Martin, C.L.; Moss, C.; Mumford, A.; Ouwehand, W.H.; Park, S.M.; Riggs, E.R.; Scott, R.H.; Sisodiya, S.; Vooren, S. van der; Wapner, R.J.; Wilkie, A.O.; Wright, C.F.; Silfhout, A.T. van; Leeuw, N. de; Vries, B. de; Washingthon, N.L.; Smith, C.L.; Westerfield, M.; Schofield, P.; Ruef, B.J.; Gkoutos, G.V.; Haendel, M.; Smedley, D.; Lewis, S.E.; Robinson, P.N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have d

  7. 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

  8. Random sample consensus combined with partial least squares regression (RANSAC-PLS) for microbial metabolomics data mining and phenotype improvement.

    Science.gov (United States)

    Teoh, Shao Thing; Kitamura, Miki; Nakayama, Yasumune; Putri, Sastia; Mukai, Yukio; Fukusaki, Eiichiro

    2016-08-01

    In recent years, the advent of high-throughput omics technology has made possible a new class of strain engineering approaches, based on identification of possible gene targets for phenotype improvement from omic-level comparison of different strains or growth conditions. Metabolomics, with its focus on the omic level closest to the phenotype, lends itself naturally to this semi-rational methodology. When a quantitative phenotype such as growth rate under stress is considered, regression modeling using multivariate techniques such as partial least squares (PLS) is often used to identify metabolites correlated with the target phenotype. However, linear modeling techniques such as PLS require a consistent metabolite-phenotype trend across the samples, which may not be the case when outliers or multiple conflicting trends are present in the data. To address this, we proposed a data-mining strategy that utilizes random sample consensus (RANSAC) to select subsets of samples with consistent trends for construction of better regression models. By applying a combination of RANSAC and PLS (RANSAC-PLS) to a dataset from a previous study (gas chromatography/mass spectrometry metabolomics data and 1-butanol tolerance of 19 yeast mutant strains), new metabolites were indicated to be correlated with tolerance within certain subsets of the samples. The relevance of these metabolites to 1-butanol tolerance were then validated from single-deletion strains of corresponding metabolic genes. The results showed that RANSAC-PLS is a promising strategy to identify unique metabolites that provide additional hints for phenotype improvement, which could not be detected by traditional PLS modeling using the entire dataset. PMID:26861498

  9. The Cognitive Phenotype of Spina Bifida Meningomyelocele

    Science.gov (United States)

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory…

  10. Distribution of phenotypes among Bacillus thuringiensis strains

    Science.gov (United States)

    An extensive collection of Bacillus thuringiensis isolates from around the world were phenotypically profiled using standard biochemical tests. Six phenotypic traits occurred in 20-86% of the isolates and were useful in distinguishing isolates: production of urease (U; 20.5% of isolates), hydrolysis...

  11. MORPHO-MOLECULAR SCREENING OF RICE (ORYZA SATIVA L. GENOTYPES AT SEEDLING STAGE FOR SALT TOLERANCE

    Directory of Open Access Journals (Sweden)

    Ali Julfiker Md. Masud

    2014-10-01

    Full Text Available Providing adequate food to meet an escalating population is one of the gravest problems the humankind is now facing. To resolve this crisis identification of salt tolerant rice variety is very vital. So, in this research, ten rice genotypes were used to screen salinity tolerance at the seedling stage in hydroponic system using SSR markers. Salinity screening was done at glasshouse following IRRI standard protocol using two setups of salinized and non-salinized conditions. Genotypes under controlled condition had longer root and shoot length then salt stress genotypes. Parental polymorphism survey was done with ten SSR markers viz., RM336, RM510, RM7075, RM407, RM3201b, RM10748, AP3206f, RM3412, RM585, RM11504 and all were selected to evaluate salt tolerance in rice genotypes. The number of alleles per locus ranged from 3 (AP3206f to 9 (RM336, with an average of 6.1 alleles across 10 loci obtained in the study. The polymorphic information content values ranged from of 0.54 (AP3206f to a high of 0.86 (RM336 with an average of 0.74. The pair-wise comparisons of Nei’s (1973 genetic distance (D between varieties were computed from combined data for the 10 primers, ranged from 0.30 to 0.90 with an average of 0.86, while the similarity index based analysis ranged from 0.00 to 0.70. Finally, the FL-478, FL-378, Binadhan-8 and Binadhan-10 were selected as salt tolerant because they showed tolerance in phenotypic analysis. These phenotypically selected tolerant genotypes could be used for the selection of suitable parents and development of salt tolerant rice varieties.

  12. Isolation of prostrate turfgrass mutants via screening of dwarf phenotype and characterization of a perennial ryegrass prostrate mutant.

    Science.gov (United States)

    Chen, Junmei; Thammina, Chandra; Li, Wei; Yu, Hao; Yer, Huseyin; El-Tanbouly, Rania; Marron, Manon; Katin-Grazzini, Lorenzo; Chen, Yongqin; Inguagiato, John; McAvoy, Richard J; Guillard, Karl; Zhang, Xian; Li, Yi

    2016-01-01

    Prostrate turf varieties are desirable because of their increased low mowing tolerance, heat resistance, traffic resistance and ground coverage compared with upright varieties. Mutation breeding may provide a powerful tool to create prostrate varieties, but there are no simple, straightforward methods to screen for such mutants. Elucidation of the molecular basis of the major 'green revolution' traits, dwarfism and semi-dwarfism, guided us to design a simple strategy for isolating dwarf mutants of perennial ryegrass (Lolium perenne L.). We have shown that gamma-ray-mediated dominant dwarf mutants can be easily screened for at the three-leaf stage. About 10% of dwarf mutant lines also displayed a prostrate phenotype at mature stages (>10 tillers). One prostrate line, Lowboy I, has been characterized in detail. Lowboy I had significantly shorter canopy, leaf blade and internode lengths compared with wild type. Lowboy I also exhibited greater tolerance to low mowing stress than wild type. Exogenous gibberellic acid (GA) restored Lowboy I to a wild-type phenotype, indicating that the dwarf and prostrate phenotypes were both due to GA deficiency. We further showed that phenotypes of Lowboy I were dominant and stably inherited through sexual reproduction. Prostrate turfgrass mutants are difficult to screen for because the phenotype is not observed at young seedling stages, therefore our method represents a simple strategy for easily isolating prostrate mutants. Furthermore, Lowboy I may provide an outstanding germplasm for breeding novel prostrate perennial ryegrass cultivars. PMID:26955481

  13. Improved renal ischemia tolerance in females influences kidney transplantation outcomes.

    Science.gov (United States)

    Aufhauser, David D; Wang, Zhonglin; Murken, Douglas R; Bhatti, Tricia R; Wang, Yanfeng; Ge, Guanghui; Redfield, Robert R; Abt, Peter L; Wang, Liqing; Svoronos, Nikolaos; Thomasson, Arwin; Reese, Peter P; Hancock, Wayne W; Levine, Matthew H

    2016-05-01

    Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance. PMID:27088798

  14. Metabolomic phenotyping of af cloned pig model

    DEFF Research Database (Denmark)

    Clausen, Morten Rahr; Christensen, Kirstine Lykke; Hedemann, Mette Skou;

    2011-01-01

    Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and...... possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal...... outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n...

  15. Adjusting phenotypes by noise control.

    Directory of Open Access Journals (Sweden)

    Kyung H Kim

    2012-01-01

    Full Text Available Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks.

  16. 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...

  17. 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)

  18. Commentary - Physiological variation and phenotypic plasticity: a response to 'Platicity in arthropod cryotypes' by Hawes and Bale

    DEFF Research Database (Denmark)

    Chown, S.L.; Sørensen, Jesper Givskov; Sinclair, B.J.

    2008-01-01

    In a recent publication, Hawes and Bale provide an extended discussion of phenotypic plasticity in the context of low temperature responses of animals. They argue that phenotypic plasticity may be partitioned phylogenetically at several levels and go on to explore these levels, and cold hardiness......' should not be used. We also show that a definition of strategies as cryotypes is not useful and that the hypothesis about the relationship between evolutionary derivation and extent of plasticity in freeze-avoiding vs freeze-tolerant species is not supported by current evidence....

  19. Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes

    DEFF Research Database (Denmark)

    Ketterer, Caroline; Müssig, Karsten; Heni, Martin;

    2011-01-01

    tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency =0.05) within the TRPM5 locus (D' = 1.0; r² = 0.8). Rs800344......The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic ß-cell dysfunction. We...

  20. Immune tolerance in radiation chimeras

    International Nuclear Information System (INIS)

    Establishment of immune tolerance in radiation chimeras and the mechanism of maintaining it were discussed from certain points. Semiallogeneic radiation chimeras are mostly of long-living, and the hematopoietic organ of this individual consists mainly of the cells derived from the marrow donor, i. e., F1-type cells. F1-type lymphocytes can distinguish parental strain cells from themselves. In these chimeras, a F1-skin graft maintains to be fresh as long as the host is alive, showing immune tolerance effective through its life. In establishment and maintenance of this immune tolerance, the suppressing mechanism of host-type or F1-type seems to be involved. The allogeneic radiation chimera has very poor long-survival rate compared with that of the semiallogeneic radiation chimera. To raise this survival rate, efforts are now being made from the immunological point of view. (Ueda, J.)

  1. Fault-Tolerant Heat Exchanger

    Science.gov (United States)

    Izenson, Michael G.; Crowley, Christopher J.

    2005-01-01

    A compact, lightweight heat exchanger has been designed to be fault-tolerant in the sense that a single-point leak would not cause mixing of heat-transfer fluids. This particular heat exchanger is intended to be part of the temperature-regulation system for habitable modules of the International Space Station and to function with water and ammonia as the heat-transfer fluids. The basic fault-tolerant design is adaptable to other heat-transfer fluids and heat exchangers for applications in which mixing of heat-transfer fluids would pose toxic, explosive, or other hazards: Examples could include fuel/air heat exchangers for thermal management on aircraft, process heat exchangers in the cryogenic industry, and heat exchangers used in chemical processing. The reason this heat exchanger can tolerate a single-point leak is that the heat-transfer fluids are everywhere separated by a vented volume and at least two seals. The combination of fault tolerance, compactness, and light weight is implemented in a unique heat-exchanger core configuration: Each fluid passage is entirely surrounded by a vented region bridged by solid structures through which heat is conducted between the fluids. Precise, proprietary fabrication techniques make it possible to manufacture the vented regions and heat-conducting structures with very small dimensions to obtain a very large coefficient of heat transfer between the two fluids. A large heat-transfer coefficient favors compact design by making it possible to use a relatively small core for a given heat-transfer rate. Calculations and experiments have shown that in most respects, the fault-tolerant heat exchanger can be expected to equal or exceed the performance of the non-fault-tolerant heat exchanger that it is intended to supplant (see table). The only significant disadvantages are a slight weight penalty and a small decrease in the mass-specific heat transfer.

  2. Integrated genomics, physiology and breeding approaches for improving drought tolerance in crops

    OpenAIRE

    Mir, Reyazul Rouf; Zaman-Allah, Mainassara; Sreenivasulu, Nese; TRETHOWAN, Richard; Rajeev K. Varshney

    2012-01-01

    Drought is one of the most serious production constraint for world agriculture and is projected to worsen with anticipated climate change. Inter-disciplinary scientists have been trying to understand and dissect the mechanisms of plant tolerance to drought stress using a variety of approaches; however, success has been limited. Modern genomics and genetic approaches coupled with advances in precise phenotyping and breeding methodologies are expected to more effectively unravel the genes and m...

  3. Tolerance of Escherichia coli to Fluoroquinolone Antibiotics Depends on Specific Components of the SOS Response Pathway

    OpenAIRE

    Theodore, Alyssa; Lewis, Kim; Vulić, Marin

    2013-01-01

    Bacteria exposed to bactericidal fluoroquinolone (FQ) antibiotics can survive without becoming genetically resistant. Survival of these phenotypically resistant cells, commonly called “persisters,” depends on the SOS gene network. We have examined mutants in all known SOS-regulated genes to identify functions essential for tolerance in Escherichia coli. The absence of DinG and UvrD helicases and the Holliday junction processing enzymes RuvA and RuvB leads to a decrease in survival. Analysis o...

  4. Mathematical model of cylindrical form tolerance

    Institute of Scientific and Technical Information of China (English)

    蔡敏; 杨将新; 吴昭同

    2004-01-01

    Tolerance is essential for integration of CAD and CAM.Unfortunately,the meaning of tolerances in the national standard is expressed in graphical and language forms and is not adaptable for expression,processing and data transferring with computers.How to interpret its semantics is becoming a focus of relevant studies.This work based on the mathematical definition of form tolerance in ANSI Y 14.5.1 M-1994,established the mathematical model of form tolerance for cylindrical feature.First,each tolerance in the national standard was established by vector equation.Then on the foundation of tolerance's mathematical definition theory,each tolerance zone's mathematical model was established by inequality based on degrees of feature.At last the variance area of each tolerance zone is derived.This model can interpret the semantics of form tolerance exactly and completely.

  5. Building Intrusion Tolerant Software System

    Institute of Scientific and Technical Information of China (English)

    PENG Wen-ling; WANG Li-na; ZHANG Huan-guo; CHEN Wei

    2005-01-01

    In this paper, we describe and analyze the hypothesis about intrusion tolerance software system, so that it can provide an intended server capability and deal with the impacts caused by the intruder exploiting the inherent security vulnerabilities. We present some intrusion tolerance technology by exploiting N-version module threshold method in constructing multilevel secure software architecture, by detecting with hash value, by placing an "antigen" word next to the return address on the stack that is similar to human immune system, and by adding "Honey code" nonfunctional code to disturb intruder, so that the security and the availability of the software system are ensured.

  6. Anhydrobiosis and Freezing-Tolerance

    DEFF Research Database (Denmark)

    McGill, Lorraine; Shannon, Adam; Pisani, Davide; Felix, Marie-Anne; Ramløv, Hans; Dix, Ilona; Wharton, David; Burnell, Ann

    2015-01-01

    Panagrolaimus strains from tropical, temperate, continental and polar habitats and we analysed their phylogenetic relationships. We found that several other Panagrolaimus isolates can also survive freezing when fully hydrated and that tissue extracts from these freezing-tolerant nematodes can inhibit the growth...... an evolved response to polar conditions. Thus we suggest that the colonization of Antarctica by P. davidi and of Surtsey by P. superbus may be examples of recent “ecological fitting” of freezing-tolerant anhydrobiotic propagules to the respective abiotic conditions in Ross Island and Surtsey...

  7. Methods to establish flaw tolerances

    International Nuclear Information System (INIS)

    Three conventional methods used to establish flaw tolerances are compared with new approaches using fracture mechanics. The conventional methods are those based on (a) non-destructive testing methods; (b) fabrication and quality assurance experience; and (c) service and damage experience. Pre-requisites of fracture mechanics methods are outlined, and summaries given of linear elastic mechanics (LEFM) and elastoplastic fracture mechanics (EPFM). The latter includes discussion of C.O.D.(crack opening displacement), the J-integral and equivalent energy. Proposals are made for establishing flaw tolerances. (U.K.)

  8. Tolerating extremism : to what extent should intolerance be tolerated?

    NARCIS (Netherlands)

    Guiora, Amos Neuser

    2013-01-01

    In discussing extremism, the key questions are: to whom is a duty owed and what are the limits of intolerance that are to be tolerated? Answering these questions requires examining limits and rights; analyzing them in the context of extremism is the ‘core’ of this book. While freedom of speech and f

  9. PHENOTYPIC TRAITS IN ZAGORJE TURKEY

    Directory of Open Access Journals (Sweden)

    Z. Janječić

    2007-06-01

    Full Text Available Production of turkeys in the region of Hrvatsko zagorje began in second half of 16th century, when there was a little influence of other turkey breeds from other region. Recently, interest for protection and preservation of autochthonous poultry breeds in Croatia is growing and in that sense this investigation was set to determine the phenotypic traits of Zagorje turkey. One hundred 10-month old turkeys (5 males and 20 females of four strains (bronze, black, grey and pale were measured, while egg production data were collected by a poll among the breeders. Average body weight of bronze, black, grey and pale strain males were 7.08, 6.88, 6.10 and 6.09 kg, respectively, while in females the average values were 4.02, 4.07, 3.63, and 3.68 kg. Generally, according to body measures of male birds, other than body weight, of all of the strains of Zagorje turkey, the black one is the biggest, as it had the highest values for body length, length of sternum, length of drumstick, length of shank, depth of chest and head measures. At the same time, the bronze strain had the highest value for carcass width. Body measures mentioned previously were not so different in females. Number of reared chicks was lowest in the pale strain. From the body measures assessed it is possible to conclude that Zagorje turkeys are rather uniform within the strain but differences in most of the breed traits are present between the strains, especially in males of bronze and black strain, when compared to gray and pale strain.

  10. Metabolomic phenotyping of a cloned pig model

    Directory of Open Access Journals (Sweden)

    Callesen Henrik

    2011-08-01

    Full Text Available Abstract Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5 was for the first time elucidated by nuclear magnetic resonance (NMR-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6 by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals.

  11. Calculation of tolerances in accelerating structures

    International Nuclear Information System (INIS)

    A method is suggested for calculating tolerances for similar elements of an accelerating-focusing channel of a charged particle linac the particle dynamics in which is described by linear or non-linear equations. Tolerances for each drift tube of the accelerating structure with modified variable-phase focusing are determined with respect to tolerances for the output parameters of an accelerated beam at preset lengths of drift tubes. The tolerances obtained in supposition of equal effects, equal tolerances and those accounting for the cost of fabrication and assembling of the elements of the structure are compared. The algorithm suggested can also be used for calculating tolerances in structures with hard focusing

  12. Improving isopropanol tolerance and production of Clostridium beijerinckii DSM 6423 by random mutagenesis and genome shuffling.

    Science.gov (United States)

    Gérando, H Máté de; Fayolle-Guichard, F; Rudant, L; Millah, S K; Monot, F; Ferreira, Nicolas Lopes; López-Contreras, A M

    2016-06-01

    Random mutagenesis and genome shuffling was applied to improve solvent tolerance and isopropanol/butanol/ethanol (IBE) production in the strictly anaerobic bacteria Clostridium beijerinckii DSM 6423. Following chemical mutagenesis with N-methyl-N-nitro-N-nitrosoguanidine (NTG), screening of putatively improved strains was done by submitting the mutants to toxic levels of inhibitory chemicals or by screening for their tolerance to isopropanol (>35 g/L). Suicide substrates, such as ethyl or methyl bromobutyrate or alcohol dehydrogenase inhibitors like allyl alcohol, were tested and, finally, 36 mutants were isolated. The fermentation profiles of these NTG mutant strains were characterized, and the best performing mutants were used for consecutive rounds of genome shuffling. Screening of strains with further enhancement in isopropanol tolerance at each recursive shuffling step was then used to spot additionally improved strains. Three highly tolerant strains were finally isolated and able to withstand up to 50 g/L isopropanol on plates. Even if increased tolerance to the desired end product was not always accompanied by higher production capabilities, some shuffled strains showed increased solvent titers compared to the parental strains and the original C. beijerinckii DSM 6423. This study confirms the efficiency of genome shuffling to generate improved strains toward a desired phenotype such as alcohol tolerance. This tool also offers the possibility of obtaining improved strains of Clostridium species for which targeted genetic engineering approaches have not been described yet. PMID:26852409

  13. Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin Resistance by Increasing Glycosuria.

    Science.gov (United States)

    Chhabra, Kavaljit H; Adams, Jessica M; Fagel, Brian; Lam, Daniel D; Qi, Nathan; Rubinstein, Marcelo; Low, Malcolm J

    2016-03-01

    Hypothalamic proopiomelanocortin (POMC) is essential for the physiological regulation of energy balance; however, its role in glucose homeostasis remains less clear. We show that hypothalamic arcuate nucleus (Arc)POMC-deficient mice, which develop severe obesity and insulin resistance, unexpectedly exhibit improved glucose tolerance and remain protected from hyperglycemia. To explain these paradoxical phenotypes, we hypothesized that an insulin-independent pathway is responsible for the enhanced glucose tolerance. Indeed, the mutant mice demonstrated increased glucose effectiveness and exaggerated glycosuria relative to wild-type littermate controls at comparable blood glucose concentrations. Central administration of the melanocortin receptor agonist melanotan II in mutant mice reversed alterations in glucose tolerance and glycosuria, whereas, conversely, administration of the antagonist Agouti-related peptide (Agrp) to wild-type mice enhanced glucose tolerance. The glycosuria of ArcPOMC-deficient mice was due to decreased levels of renal GLUT 2 (rGLUT2) but not sodium-glucose cotransporter 2 and was associated with reduced renal catecholamine content. Epinephrine treatment abolished the genotype differences in glucose tolerance and rGLUT2 levels, suggesting that reduced renal sympathetic nervous system (SNS) activity is the underlying mechanism for the observed glycosuria and improved glucose tolerance in ArcPOMC-deficient mice. Therefore, the ArcPOMC-SNS-rGLUT2 axis is potentially an insulin-independent therapeutic target to control diabetes. PMID:26467632

  14. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

    DEFF Research Database (Denmark)

    Sparsø, T; Andersen, G; Albrechtsen, Anders; Jørgensen, T; Borch-Johnsen, K; Sandbaek, A; Lauritzen, T; Wasson, J; Permutt, M A; Glaser, B; Madsbad, S; Pedersen, Oluf; Hansen, T

    2008-01-01

    AIM/HYPOTHESIS: Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucose-tolerant people and in individuals with abnormal glucose regulation. METHODS: The type 2 diabetes-associated WFS1 variant rs7...

  15. QTL Analysis of Anoxic Tolerance at Seedling Stage in Rice

    Institute of Scientific and Technical Information of China (English)

    WANG Yang; GUO Yuan; HONG De-lin

    2010-01-01

    Coleoptile lengths of 7-day-old seedlings under anoxic stress and normal conditions were investigated in two permanently segregated populations and their parents in rice (Oryza sativa L.). Using anoxic response index, a ratio of coleoptile length under anoxic stress to coleoptile length under normal conditions, as an indicator of seedling anoxic tolerance (SAT), QTLs for SAT were detected. Two loci controlling SAT, designated as qSAT-2-R and qSAT-7-R, were detected in a recombinant inbred line (RIL) population (247 lines) derived from a cross between Xiushui 79 (japonica variety) and C Bao (japonica restorer line). qSAT-2-R, explaining 8.7% of the phenotype variation, was tightly linked with the SSR marker RM525. qSAT-7-R, explaining 9.8% of the phenotype variation, was tightly linked with the marker RM418. The positive alleles of the two loci came from C Bao. Six loci controlling SAT, designated as qSAT-2-B, qSAT-3-B, qSAT-5-B, qSAT-8-B, qSAT-9-B and qSAT-12-B, were detected in a backcross inbred line (BIL) population (98 lines) derived from a backcross of Nipponbare (japonica)/Kasalath (indica)//Nipponbare (japonica). The positive alleles of qSAT-2-B, qSAT-3-B and qSAT-9-B, which explained 16.2%, 11.4% and 9.5% of the phenotype variation, respectively, came from Nipponbare. Besides, the positive alleles of qSAT-5-B, qSAT-8-B and qSAT-12-B, which explained 7.3%, 5.8% and 14.0% of the phenotype variation, respectively, were from Kasalath.

  16. When Should Sects be Tolerated?

    DEFF Research Database (Denmark)

    Hvithamar, Annika

    Jehovas vidners kontroverser med majoritetssamfundet gør dem til et godt test-case for tolerance. I artiklen bruges udviklingen af bevægelsens syn på blodstransfusioner til at diskutere, hvordan institutionaliseringen af en minoritetsbevægelse får kontroversernes styrke til at mindskes, men også ...

  17. B cells and immunological tolerance.

    Science.gov (United States)

    Manjarrez-Orduño, Nataly; Quách, Tâm D; Sanz, Iñaki

    2009-02-01

    Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B-cell depletion therapy may be, to a large extent, determined by the functional balance between different B-cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B-cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we first discuss current knowledge of B-cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B-cell gain-of-pathogenic function (or a B-cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B-cell pathogenic and protective functions. PMID:19148217

  18. Dicamba Tolerant Soybean MON 87708

    OpenAIRE

    Directorate, Issued by Health Canada's Food

    2014-01-01

    Health Canada has notified Monsanto Canada Inc. that it has no objection to the sale of food derived from Dicamba Tolerant Soybean MON 87708. The Department conducted a comprehensive assessment of this soybean event according to its Guidelines for the Safety Assessment of Novel Foods. These Guidelines are based upon internationally accepted principles for establishing the safety of foods with novel traits.

  19. Biocatalysts with enhanced inhibitor tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shihui; Linger, Jeffrey; Franden, Mary Ann; Pienkos, Philip T.; Zhang, Min

    2015-12-08

    Disclosed herein are biocatalysts for the production of biofuels, including microorganisms that contain genetic modifications conferring tolerance to growth and fermentation inhibitors found in many cellulosic feedstocks. Methods of converting cellulose-containing materials to fuels and chemicals, as well as methods of fermenting sugars to fuels and chemicals, using these biocatalysts are also disclosed.

  20. Toleration, Multiculturalism and Mistaken Belief

    Science.gov (United States)

    Standish, Paul

    2006-01-01

    Doubts have been expressed about the virtue of toleration, especially in view of what some have seen as its complicity with a morality of anything goes. More rigorous arguments have been provided by Peter Gardner and Harvey Siegel against the relativism evident in certain versions of multiculturalism and in the new religious studies. This article…

  1. Genetically engineered Rice with transcription factor DREB genes for abiotic stress tolerance(abstract)

    International Nuclear Information System (INIS)

    Water stress (drought and Salinity) is the most severe limitation to rice productivity. Several breeding approaches (MAS, QTL) applied to suitable genotypes are in place at IRRI and elsewhere. Phenotyping of water stress tolerance is in progress with potential predictability. Dr. Shinozaki's group has cloned a number of transcription factor genes, which have been shown to work in Arabidopsis to achieve drought, cold, and salinity tolerant plants. None of these genes have as yet displayed their potential functioning in rice. Genetic engineering aims at cross talk between different stress signaling pathways leading to stress tolerance. Osmotic Adjustment (OA) is an effective component of abiotic stress (drought and salinity) tolerance in many plants including rice. When plant experiences water stress, OA contributes to turgor maintenance of both shoots and roots. Conventional breeding could not achieve the OA in rice excepting a few rice cultivars, which are partially adapted to water-stress conditions. Several stress-related genes have now been cloned and transferred in to enhance the osmolytes and some transgenic lines showed increased tolerance to osmotic stress. A few strategies could be effectively deployed for a better understanding of water-stress tolerance in rice and to develop transgenic rice, which can survive for a critical period of water-stress conditions: 1) Switching on of transcription factor regulating the expression of several genes related to abiotic stress, 2) Use of a suitable stress inducible promoter driving the target gene for an efficient and directed expression in plants, 3) Understanding of phenotyping and GxE in a given environment, 4) Selection of a few adaptive rice cultivars suitable in drought/salinity prone areas, 5) Microarray, proteomics, QTL and MAS may expedite the cloning and characterizing the stress induced genes, and 6) Finally, the efficient transformation system for generating a large number of transgenic rice of different

  2. Resistance and Tolerance to Tropodithietic Acid, an Antimicrobial in Aquaculture, Is Hard To Select

    DEFF Research Database (Denmark)

    Porsby, Cisse Hedegaard; Webber, Mark A.; Nielsen, Kristian Fog;

    2011-01-01

    development of TDA resistance. A bacterial extract containing 95% TDA was effective against a range of human-pathogenic bacteria, including both Gram-negative and Gram-positive bacteria. TDA was bactericidal against Salmonella enterica serovar Typhimurium SL1344 and Staphylococcus aureus NCTC 12493 and killed......-spectrum antimicrobial in part due to the fact that enhanced tolerance is difficult to gain and that the TDA-tolerant phenotype appears to confer only low-level resistance and is very unstable....... both growing and nongrowing cells. Several experimental approaches were used to select mutants resistant to TDA or subpopulations of strains with enhanced tolerance to TDA. No approach (single exposures to TDA extract administered via different methods, screening of a transposon library for resistant...

  3. Size-symmetric competition in a shade-tolerant invasive plant

    DEFF Research Database (Denmark)

    Pan, Xiao-Yun; Weiner, Jacob; Li, Bo

    2013-01-01

    , a shade‐tolerant invasive species. Stem fragments of A. philoxeroides were grown at either low or high densities (6 vs. 24 plants per pot) under three light levels (10%, 34%, and 100% full sun). After 8 weeks, survival was 31% lower in pots with a higher initial density. Both high density and low light......Plant responses to crowding have been investigated extensively in stands of light‐demanding species, but shade‐tolerant species may react differently. In the present study, we investigated the effect of density on the mortality, size inequality, and biomass allocation of Alternanthera philoxeroides...... competition need not be size asymmetric, and suggest that tolerance to low light levels involves a reduction in phenotypic plasticity. Responses of the invasive A. philoxeroides to crowding may be an example of an invasive plant’s success in establishing dense stands of closely related individuals...

  4. Advances in functional genomics for investigating salinity stress tolerance mechanisms in cereals.

    Science.gov (United States)

    Shelden, Megan C; Roessner, Ute

    2013-01-01

    Abiotic stresses such as low water availability and high salinity are major causes of cereal crop yield losses and significantly impact on sustainability. Wheat and barley are two of the most important cereal crops (after maize and rice) and are grown in increasingly hostile environments with soil salinity and drought both expected to increase this century, reducing the availability of arable land. Barley and wheat are classified as glycophytes (salt-sensitive), yet they are more salt-tolerant than other cereal crops such as rice and so are good models for studying salt tolerance in cereals. The exploitation of genetic variation of phenotypic traits through plant breeding could significantly improve growth of cereals in salinity-affected regions, thus leading to improved crop yields. Genetic variation in phenotypic traits for abiotic stress tolerance have been identified in land races and wild germplasm but the molecular basis of these differences is often difficult to determine due to the complex genetic nature of these species. High-throughput functional genomics technologies, such as transcriptomics, metabolomics, proteomics, and ionomics are powerful tools for investigating the molecular responses of plants to abiotic stress. The advancement of these technologies has allowed for the identification and quantification of transcript/metabolites in specific cell types and/or tissues. Using these new technologies on plants will provide a powerful tool to uncovering genetic traits in more complex species such as wheat and barley and provide novel insights into the molecular mechanisms of salinity stress tolerance. PMID:23717314

  5. Advances in functional genomics for investigating salinity stress tolerance mechanisms in cereals

    Directory of Open Access Journals (Sweden)

    Megan C Shelden

    2013-05-01

    Full Text Available Abiotic stresses such as low water availability and high salinity are major causes of cereal crop yield losses and significantly impact on sustainability. Wheat and barley are two of the most important cereal crops (after maize and rice and are grown in increasingly hostile environments with soil salinity and drought both expected to increase this century, reducing the availability of arable land. Barley and wheat are classified as glycophytes (salt-sensitive, yet they are more salt-tolerant than other cereal crops such as rice and so are good models for studying salt-tolerance in cereals. The exploitation of genetic variation of phenotypic traits through plant breeding could significantly improve growth of cereals in salinity-affected regions, thus leading to improved crop yields. Genetic variation in phenotypic traits for abiotic stress tolerance have been identified in land races and wild germplasm but the molecular basis of these differences is often difficult to determine due to the complex genetic nature of these species. High-throughput functional genomics technologies, such as transcriptomics, metabolomics, proteomics and ionomics are powerful tools for investigating the molecular responses of plants to abiotic stress. The advancement of these technologies has allowed for the identification and quantification of transcript /metabolites in specific cell types and/or tissues. Using these new technologies on plants will provide a powerful tool to uncovering genetic traits in more complex species such as wheat and barley and provide novel insights into the molecular mechanisms of salinity stress tolerance.

  6. Identification of Crowding Stress Tolerance Co-Expression Networks Involved in Sweet Corn Yield

    Science.gov (United States)

    Choe, Eunsoo; Drnevich, Jenny; Williams, Martin M.

    2016-01-01

    Tolerance to crowding stress has played a crucial role in improving agronomic productivity in field corn; however, commercial sweet corn hybrids vary greatly in crowding stress tolerance. The objectives were to 1) explore transcriptional changes among sweet corn hybrids with differential yield under crowding stress, 2) identify relationships between phenotypic responses and gene expression patterns, and 3) identify groups of genes associated with yield and crowding stress tolerance. Under conditions of crowding stress, three high-yielding and three low-yielding sweet corn hybrids were grouped for transcriptional and phenotypic analyses. Transcriptional analyses identified from 372 to 859 common differentially expressed genes (DEGs) for each hybrid. Large gene expression pattern variation among hybrids and only 26 common DEGs across all hybrid comparisons were identified, suggesting each hybrid has a unique response to crowding stress. Over-represented biological functions of DEGs also differed among hybrids. Strong correlation was observed between: 1) modules with up-regulation in high-yielding hybrids and yield traits, and 2) modules with up-regulation in low-yielding hybrids and plant/ear traits. Modules linked with yield traits may be important crowding stress response mechanisms influencing crop yield. Functional analysis of the modules and common DEGs identified candidate crowding stress tolerant processes in photosynthesis, glycolysis, cell wall, carbohydrate/nitrogen metabolic process, chromatin, and transcription regulation. Moreover, these biological functions were greatly inter-connected, indicating the importance of improving the mechanisms as a network. PMID:26796516

  7. Identification of Crowding Stress Tolerance Co-Expression Networks Involved in Sweet Corn Yield.

    Science.gov (United States)

    Choe, Eunsoo; Drnevich, Jenny; Williams, Martin M

    2016-01-01

    Tolerance to crowding stress has played a crucial role in improving agronomic productivity in field corn; however, commercial sweet corn hybrids vary greatly in crowding stress tolerance. The objectives were to 1) explore transcriptional changes among sweet corn hybrids with differential yield under crowding stress, 2) identify relationships between phenotypic responses and gene expression patterns, and 3) identify groups of genes associated with yield and crowding stress tolerance. Under conditions of crowding stress, three high-yielding and three low-yielding sweet corn hybrids were grouped for transcriptional and phenotypic analyses. Transcriptional analyses identified from 372 to 859 common differentially expressed genes (DEGs) for each hybrid. Large gene expression pattern variation among hybrids and only 26 common DEGs across all hybrid comparisons were identified, suggesting each hybrid has a unique response to crowding stress. Over-represented biological functions of DEGs also differed among hybrids. Strong correlation was observed between: 1) modules with up-regulation in high-yielding hybrids and yield traits, and 2) modules with up-regulation in low-yielding hybrids and plant/ear traits. Modules linked with yield traits may be important crowding stress response mechanisms influencing crop yield. Functional analysis of the modules and common DEGs identified candidate crowding stress tolerant processes in photosynthesis, glycolysis, cell wall, carbohydrate/nitrogen metabolic process, chromatin, and transcription regulation. Moreover, these biological functions were greatly inter-connected, indicating the importance of improving the mechanisms as a network. PMID:26796516

  8. Interact to survive: Phyllobacterium brassicacearum improves Arabidopsis tolerance to severe water deficit and growth recovery.

    Directory of Open Access Journals (Sweden)

    Justine Bresson

    Full Text Available Mutualistic bacteria can alter plant phenotypes and confer new abilities to plants. Some plant growth-promoting rhizobacteria (PGPR are known to improve both plant growth and tolerance to multiple stresses, including drought, but reports on their effects on plant survival under severe water deficits are scarce. We investigated the effect of Phyllobacterium brassicacearum STM196 strain, a PGPR isolated from the rhizosphere of oilseed rape, on survival, growth and physiological responses of Arabidopsis thaliana to severe water deficits combining destructive and non-destructive high-throughput phenotyping. Soil inoculation with STM196 greatly increased the survival rate of A. thaliana under several scenarios of severe water deficit. Photosystem II efficiency, assessed at the whole-plant level by high-throughput fluorescence imaging (Fv/Fm, was related to the probability of survival and revealed that STM196 delayed plant mortality. Inoculated surviving plants tolerated more damages to the photosynthetic tissues through a delayed dehydration and a better tolerance to low water status. Importantly, STM196 allowed a better recovery of plant growth after rewatering and stressed plants reached a similar biomass at flowering than non-stressed plants. Our results highlight the importance of plant-bacteria interactions in plant responses to severe drought and provide a new avenue of investigations to improve drought tolerance in agriculture.

  9. INTEGRATION OF EIT, SOIL STRUCTURE AND PLANT PHYSIOLOGYMODELS FOR 3D IMAGING OF CROP ROOT FUNCTION PHENOTYPE

    OpenAIRE

    Hayes, Robert Richard

    2015-01-01

    Climate change necessitates breeding programmes for the development of plant varieties that are tolerant to drought and other environmental stresses. Rapid identification of new plant varieties that will thrive in future climates is increasingly important. Presently, above soil features are monitored in industrial greenhouses and field trials. Indicators of preferential genetic traits are often based on loosely related features (phenotypes) such as an extra ear of corn on a maize plant. The r...

  10. 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

  11. 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.

  12. PpCBF3 from Cold-Tolerant Kentucky Bluegrass Involved in Freezing Tolerance Associated with Up-Regulation of Cold-Related Genes in Transgenic Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Lili Zhuang

    Full Text Available Dehydration-Responsive Element Binding proteins (DREB/C-repeat (CRT Binding Factors (CBF have been identified as transcriptional activators during plant responses to cold stress. The objective of this study was to determine the physiological roles of a CBF gene isolated from a cold-tolerant perennial grass species, Kentucky bluegrass (Poa pratensis L., which designated as PpCBF3, in regulating plant tolerance to freezing stress. Transient transformation of Arabidopsis thaliana mesophyll protoplast with PpCBF3-eGFP fused protein showed that PpCBF3 was localized to the nucleus. RT-PCR analysis showed that PpCBF3 was specifically induced by cold stress (4°C but not by drought stress [induced by 20% polyethylene glycol 6000 solution (PEG-6000] or salt stress (150 mM NaCl. Transgenic Arabidopsis overexpressing PpCBF3 showed significant improvement in freezing (-20°C tolerance demonstrated by a lower percentage of chlorotic leaves, lower cellular electrolyte leakage (EL and H2O2 and O2.- content, and higher chlorophyll content and photochemical efficiency compared to the wild type. Relative mRNA expression level analysis by qRT-PCR indicated that the improved freezing tolerance of transgenic Arabidopsis plants overexpressing PpCBF3 was conferred by sustained activation of downstream cold responsive (COR genes. Other interesting phenotypic changes in the PpCBF3-transgenic Arabidopsis plants included late flowering and slow growth or 'dwarfism', both of which are desirable phenotypic traits for perennial turfgrasses. Therefore, PpCBF3 has potential to be used in genetic engineering for improvement of turfgrass freezing tolerance and other desirable traits.

  13. Glucose tolerance test - non-pregnant

    Science.gov (United States)

    Oral glucose tolerance test - non-pregnant; OGTT - non-pregnant; Diabetes - glucose tolerance test ... to diagnose diabetes in people who are not pregnant are: Fasting blood glucose level: diabetes is diagnosed ...

  14. Metabolomic phenotyping of a cloned pig model

    DEFF Research Database (Denmark)

    Clausen, Morten Rahr; Christensen, Kirstine Lykke; Hedemann, Mette Skou;

    2011-01-01

    Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and...... established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals....... possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal...

  15. Phenotypic profiles of Armenian grape cultivars

    Directory of Open Access Journals (Sweden)

    Aroutiounian Rouben

    2015-01-01

    Full Text Available The conservation and sustainable use of grapevine biodiversity in Armenia is particularly important due to the large number of traditional local varieties. Being partially different from European grapevine gene pool, the material of Armenian local cultivars significantly contributes to the understanding of the genetic variation and is valuable source for target selection. During last years many Armenian grapevine cultivars have been already described and their genotypes determined, but some local varieties and wild accessions remain unidentified and their phenotypic characteristics overlooked. The comprehensive analysis of phenotypes is essential for research, including genetic association studies, cultivar evaluation and selection. The goal of our research was the phenotyping on the base of reproductive, carpological and analytical characteristics of 80 Armenian aboriginal and new grape cultivars. Description of phenotypic profiles is important step towards identification and conservation of genetic resources of Armenian grapes. In future, these data can be applied for breeding of improved grape varieties targeted to fresh consumption and wine production.

  16. Mining skeletal phenotype descriptions from scientific literature.

    Directory of Open Access Journals (Sweden)

    Tudor Groza

    Full Text Available Phenotype descriptions are important for our understanding of genetics, as they enable the computation and analysis of a varied range of issues related to the genetic and developmental bases of correlated characters. The literature contains a wealth of such phenotype descriptions, usually reported as free-text entries, similar to typical clinical summaries. In this paper, we focus on creating and making available an annotated corpus of skeletal phenotype descriptions. In addition, we present and evaluate a hybrid Machine Learning approach for mining phenotype descriptions from free text. Our hybrid approach uses an ensemble of four classifiers and experiments with several aggregation techniques. The best scoring technique achieves an F-1 score of 71.52%, which is close to the state-of-the-art in other domains, where training data exists in abundance. Finally, we discuss the influence of the features chosen for the model on the overall performance of the method.

  17. Large phenotype jumps in biomolecular evolution

    CERN Document Server

    Bardou, F

    2003-01-01

    By defining the phenotype of a biopolymer by its active three-dimensional shape, and its genotype by its primary sequence, we propose a model that predicts and characterizes the statistical distribution of a population of biopolymers with a specific phenotype, that originated from a given genotypic sequence by a single mutational event. Depending on the ratio g0 that characterizes the spread of potential energies of the mutated population with respect to temperature, three different statistical regimes have been identified. We suggest that biopolymers found in nature are in a critical regime with g0 in the range 1-6, corresponding to a broad, but not too broad, phenotypic distribution resembling a truncated Levy flight. Thus the biopolymer phenotype can be considerably modified in just a few mutations.

  18. Stress-Driven Selection of Novel Phenotypes

    Science.gov (United States)

    Fox, George E.; Stepaov, Victor G.; Liu, Yamei

    2011-01-01

    A process has been developed that can confer novel properties, such as metal resistance, to a host bacterium. This same process can also be used to produce RNAs and peptides that have novel properties, such as the ability to bind particular compounds. It is inherent in the method that the peptide or RNA will behave as expected in the target organism. Plasmid-born mini-gene libraries coding for either a population of combinatorial peptides or stable, artificial RNAs carrying random inserts are produced. These libraries, which have no bias towards any biological function, are used to transform the organism of interest and to serve as an initial source of genetic variation for stress-driven evolution. The transformed bacteria are propagated under selective pressure in order to obtain variants with the desired properties. The process is highly distinct from in vitro methods because the variants are selected in the context of the cell while it is experiencing stress. Hence, the selected peptide or RNA will, by definition, work as expected in the target cell as the cell adapts to its presence during the selection process. Once the novel gene, which produces the sought phenotype, is obtained, it can be transferred to the main genome to increase the genetic stability in the organism. Alternatively, the cell line can be used to produce novel RNAs or peptides with selectable properties in large quantity for separate purposes. The system allows for easy, large-scale purification of the RNAs or peptide products. The process has been reduced to practice by imposing sub-inhibitory concentrations of NiCl2 on cells of the bacterium Escherichia coli that were transformed separately with the peptide library and RNA library. The evolved resistant clones were isolated, and sequences of the selected mini-gene variants were established. Clones resistant to NiCl2 were found to carry identical plasmid variants with a functional mini-gene that specifically conferred significant nickel

  19. Identification of quantitative trait loci associated with salt tolerance at seedling stage from Oryza rufipogon

    Institute of Scientific and Technical Information of China (English)

    Lei Tian; Lubin Tan; Fengxia Liu; Hongwei Cai; Chuanqing Sun

    2011-01-01

    Soil salinity is one of the major abiotic stresses affecting plant growth and crop production.In the present study,salt tolerance at rice seedling stage was evaluated using 87 introgression lines (ILs),which were derived from a cross between an elite indica cultivar Teqing and an accession of common wild rice (Oryza rufipogon Griff.).Substantial variation was observed for four traits including salt tolerance score (STS),relative root dry weight (RRW),relative shoot dry weight (RSW) and relative total dry weight (RTW).STS was significantly positively correlated with all other three traits.A total of 15 putative quantitative trait loci (QTLs) associated with these four traits were detected using single-point analysis,which were located on chromosomes 1,2,3,6,7,9 and 10 with 8%-26% explaining the phenotypic variance.The O.rufipogon-derived alleles at 13 QTLs (86.7%) could improve the salt tolerance in the Teqing background.Four QTL clusters affecting RRW,RSW and RTW were found on chromosomes 6,7,9 and 10,respectively.Among these four QTL clusters,a major cluster including three QTLs (qRRW10,qRSW10 and qRTW10) was found near the maker RM271 on the long arm of chromosome 10,and the O.rufipogon-derived alleles at these three loci increased RRW,RSW and RTW with additive effects of 22.7%,17.3% and 18.5%,respectively,while the phenotypic variance explained by these three individual QTLs for the three traits varied from 19% to 26%.In addition,several salt tolerant ILs were selected and could be used for identifying and utilizing favorable salt tolerant genes from common wild rice and used in the salt tolerant rice breeding program.

  20. Pneumococcal pneumonia suppresses allergy development but preserves respiratory tolerance in mice.

    Science.gov (United States)

    Hartmann, Carolin; Behrendt, Ann-Kathrin; Henken, Stefanie; Wölbeling, Florian; Maus, Ulrich A; Hansen, Gesine

    2015-03-01

    Colonization with Streptococcus pneumoniae (S. pneumoniae) is associated with an increased risk for recurrent wheeze and asthma. Killed S. pneumoniae showed some potential as an effective immunomodulatory therapy in a murine model of asthma. Murine studies demonstrated protection against allergic asthma by symbiotic bacteria via triggering regulatory T cell response: treatment with killed S. pneumoniae resulted in suppressed levels of allergen-specific Th2 cytokines, while early immunization generated a protective Th1 response. We investigated the impact of lung infection with live S. pneumoniae on both the development and maintenance of allergic airway inflammation and respiratory tolerance in mice. BALB/c mice were infected intratracheally with S. pneumoniae either prior to or after tolerance or allergy were induced, using ovalbumin (OVA) as model allergen. Infection of mice with S. pneumoniae prior to sensitization or after manifestation of allergic airway inflammation suppressed the development of an allergic phenotype as judged by reduced eosinophil counts in bronchoalveolar lavage fluid, decreased IgE serum levels and Th2 cytokines, relative to non-infected allergic control mice. In contrast, infection of mice with S. pneumoniae after manifestation of allergic airway inflammation combined with late mucosal re-challenge did not affect the allergic response. Moreover, induction and maintenance of respiratory tolerance to OVA challenge were not altered in S. pneumoniae-infected mice, demonstrating that mice remained tolerant to the model allergen and were protected from the development of allergic airway inflammation regardless of the time point of infection. Our results suggest that a bacterial infection may decrease the manifestation of an allergic phenotype not only prior to sensitization but also after manifestation of allergic airway inflammation in mice, whereas both, induction and maintenance of respiratory tolerance are not affected by pneumococcal

  1. GEE for GWAS using Longitudinal Phenotype Data

    OpenAIRE

    Sitlani, Colleen M.; Rice, Kenneth M.; Lumley, Thomas; McKnight, Barbara; Cupples, L. Adrienne; Avery, Christy L; Noordam, Raymond; Stricker, Bruno H. C.; Whitsel, Eric A.; Psaty, Bruce M.

    2014-01-01

    Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here we discuss one such method – generalized estimating equations...

  2. Next Generation Sequencing Demands Next Generation Phenotyping

    OpenAIRE

    Hennekam, Raoul CM; Biesecker, Leslie G

    2012-01-01

    Next-Generation Sequencing (NGS) is the most powerful diagnostic tool since the roentgenogram. NGS will facilitate diagnosis on a massive scale –allowing interrogation of all genes in a single assay. It has been suggested that NGS will decrease the need for phenotyping in general, and medical geneticists in particular. We argue that NGS will shift focus and approach of phenotyping. We predict that NGS performed for diagnostic purposes will yield variants in several genes, and consequences of ...

  3. Phenotyping of robustness and milk quality

    OpenAIRE

    Berry, D. P.; Mcparland, S.; Bastin, Catherine; Wall, E.; Gengler, Nicolas; Soyeurt, Hélène

    2013-01-01

    A phenotype describes the outcome of the interacting development between the genotype of an individual and its specific environment throughout life. Animal breeding currently exploits large data sets of phenotypic and pedigree information to estimate the genetic merit of animals. Here we describe rapid, low-cost phenomic tools for dairy cattle. We give particular emphasis to infrared spectroscopy of milk because the necessary spectral data are already routinely available on milk samples from ...

  4. Phenotypic spandrel: absolute discrimination and ligand antagonism

    OpenAIRE

    François, Paul; Johnson, Kyle A.; Saunders, Laura N.

    2015-01-01

    We consider the general problem of absolute discrimination between categories of ligands irrespective of their concentration. An instance of this problem is immune discrimination between self and not-self. We connect this problem to biochemical adaptation, and establish that ligand antagonism - the ability of sub threshold ligands to negatively impact response - is a necessary consequence of absolute discrimination.Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a...

  5. Important discoveries from analysing bacterial phenotypes

    OpenAIRE

    Bochner, Barry R.; Giovannetti, Luciana; Viti, Carlo

    2008-01-01

    The ability to test hundreds to thousands of cellular phenotypes in a single experiment has opened up new avenues of investigation and exploration and led to important discoveries in very diverse applications of microbiological research and development. The information provided by global phenotyping is complementary to, and often more easily interpretable than information provided by global molecular analytical methods such as gene chips and proteomics. This report summarizes advances present...

  6. Bacteria under SOS evolve anticancer phenotypes

    OpenAIRE

    Weitao Tao; Dallo Shatha F

    2010-01-01

    Abstract Background The anticancer drugs, such as DNA replication inhibitors, stimulate bacterial adhesion and induce the bacterial SOS response. As a variety of bacterial mutants can be generated during SOS, novel phenotypes are likely to be selected under the drug pressure. Presentation of the hypothesis Bacteria growing with cancer cells in the presence of the replication inhibitors undergo the SOS response and evolve advantageous phenotypes for the bacteria to invade the cancer cells in o...

  7. A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

    DEFF Research Database (Denmark)

    Jensen, Lea Møller

    variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

  8. Phenex: Ontological Annotation of Phenotypic Diversity

    OpenAIRE

    Balhoff, James P.; Dahdul, Wasila M; Kothari, Cartik R.; Lapp, Hilmar; John G. Lundberg; Mabee, Paula; Midford, Peter E.; Westerfield, Monte; Vision, Todd J

    2010-01-01

    Background Phenotypic differences among species have long been systematically itemized and described by biologists in the process of investigating phylogenetic relationships and trait evolution. Traditionally, these descriptions have been expressed in natural language within the context of individual journal publications or monographs. As such, this rich store of phenotype data has been largely unavailable for statistical and computational comparisons across studies or integration with other ...

  9. Atypical disease phenotypes in pediatric ulcerative colitis

    DEFF Research Database (Denmark)

    Levine, Arie; de Bie, Charlotte I; Turner, Dan; Cucchiara, Salvatore; Sladek, Malgorzata; Murphy, M Stephen; Escher, Johanna C; Pærregaard, Anders

    2013-01-01

    Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping of...... atypical inflammatory bowel disease (IBD) patients. Our aim was to identify the prevalence of atypical disease patterns in new-onset pediatric UC using the Paris classification....

  10. QTL Mapping for Drought Tolerance at Stages of Germination and Seedling in Wheat (Triticum aestivum L.)Using a DH Population

    Institute of Scientific and Technical Information of China (English)

    HAO Zhuan-fang; CHANG Xiao-ping; GUO Xiao-jian; JING Rui-lian; LI Run-zhi; JIA Ji-zeng

    2003-01-01

    Drought is a major constraint in many wheat(Triticum aestivum L.) production regions. Quantitative trait loci (QTLs) conditioning drought tolerance at stages of germination and seedling in wheat were identified in a double haploid (DH) population derived from the cross, Hanxuan10×Lumai14, using amplified fragment length polymorphism (AFLP) and simple sequence repeat (SSR) markers. Interval mapping analysis revealed that QTLs for drought tolerance at germination stage were located on chromosomes 1B, 2B, 5A, 6B, 7A and 7B, respectively, and the most effective QTL was mapped on chromosome 2B, explaining 27.2% of phenotypic variance. The QTLs for drought tolerance at seedling stage were located on 1B, 3B and 7B, respectively, and the most effective QTL was mapped on chromosome 3B, explaining 21.6% of phenotypic variance. Their positions were different from those of QTLs conferring drought tolerance at germination stage, indicating that drought tolerance at germination stage and seedling stage was controlled by different loci. Most of the identified QTLs explained 18% or more of phenotypic variance for drought tolerance at germination and seedling stage, and would be useful in future for marker assisted selection programs and cultivar improvement.

  11. Phenotypic Evolution With and Beyond Genome Evolution.

    Science.gov (United States)

    Félix, M-A

    2016-01-01

    DNA does not make phenotypes on its own. In this volume entitled "Genes and Phenotypic Evolution," the present review draws the attention on the process of phenotype construction-including development of multicellular organisms-and the multiple interactions and feedbacks between DNA, organism, and environment at various levels and timescales in the evolutionary process. First, during the construction of an individual's phenotype, DNA is recruited as a template for building blocks within the cellular context and may in addition be involved in dynamical feedback loops that depend on the environmental and organismal context. Second, in the production of phenotypic variation among individuals, stochastic, environmental, genetic, and parental sources of variation act jointly. While in controlled laboratory settings, various genetic and environmental factors can be tested one at a time or in various combinations, they cannot be separated in natural populations because the environment is not controlled and the genotype can rarely be replicated. Third, along generations, genotype and environment each have specific properties concerning the origin of their variation, the hereditary transmission of this variation, and the evolutionary feedbacks. Natural selection acts as a feedback from phenotype and environment to genotype. This review integrates recent results and concrete examples that illustrate these three points. Although some themes are shared with recent calls and claims to a new conceptual framework in evolutionary biology, the viewpoint presented here only means to add flesh to the standard evolutionary synthesis. PMID:27282029

  12. Advanced phenotyping and phenotype data analysis for the study of plant growth and development.

    Science.gov (United States)

    Rahaman, Md Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

    2015-01-01

    Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060

  13. Increasing ideological tolerance in social psychology.

    Science.gov (United States)

    Inbar, Yoel; Lammers, Joris

    2015-01-01

    We argue that recognizing current ideological diversity in social psychology and promoting tolerance of minority views is just as important as increasing the number of non-liberal researchers. Increasing tolerance will allow individuals in the minority to express dissenting views, which will improve psychological science by reducing bias. We present four recommendations for increasing tolerance. PMID:26786671

  14. 78 FR 8407 - Endosulfan; Pesticide Tolerance

    Science.gov (United States)

    2013-02-06

    ... revoke all tolerances for endosulfan (76 FR 25281) (FRL-8870-4). Many of the tolerances were not proposed... accordingly, the tolerance was revoked on September 14, 2011 (76 FR 56648) (FRL-8883-9). The Zhejiang Chamber... defined in Executive Order 12866 entitled ``Regulatory Planning and Review'' (58 FR 51735, October 4,...

  15. 15 CFR 750.11 - Shipping tolerances.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Shipping tolerances. 750.11 Section... PROCESSING, ISSUANCE, AND DENIAL § 750.11 Shipping tolerances. (a) Applicability and use of shipping... a shipping tolerance. This section tells you, as the licensee, when you may take advantage of...

  16. 7 CFR 51.886 - Tolerances.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Tolerances. 51.886 Section 51.886 Agriculture... Standards for Grades of Table Grapes (European or Vinifera Type) 1 Tolerances § 51.886 Tolerances. (a) No... other than the allowances specified in § 51.888 or in the sampling and testing procedures of...

  17. 49 CFR 325.9 - Measurement tolerances.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Measurement tolerances. 325.9 Section 325.9... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION GENERAL REGULATIONS COMPLIANCE WITH INTERSTATE MOTOR CARRIER NOISE EMISSION STANDARDS General Provisions § 325.9 Measurement tolerances. (a) Measurement tolerances will...

  18. Selection of pigs for improved coping with health and environmental challenges: breeding for resistance or tolerance?

    Science.gov (United States)

    Guy, Sarita Z Y; Thomson, Peter C; Hermesch, Susanne

    2012-01-01

    The benefits of improved health and welfare in pigs have driven refinements in management and selection practices, one of which is the production of pig phenotypes that can maintain health and productivity by improving response against pathogens. Selection has traditionally been made for host resistance; but the alternative host defence mechanism-host tolerance-is now being considered, as breeding for disease tolerance allows maintenance of high performance across environments of increasing pathogenic load. A distinction must be made between these two mechanisms as they vary in their influence on host-pathogen interactions and pathogen evolution, and consequently on the results of breeding programs. Many pig production studies have failed to distinguish between resistance and tolerance; although a distinction may not always be possible. This article reviews current perspectives in selective breeding for disease resistance and tolerance in growing pigs, and the attendant industry implications. To assess the viability of breeding for resistance and/or tolerance for improved response to disease and other environmental challenges, we propose the use of routine farm records, instead of data measurements taken from laboratory experiments. Consequently, a number of factors need to be taken into account simultaneously for a multidimensional modeling approach. This includes not only genotype and disease variables, but also descriptors of the environment, as well as any possible interactions. It may not be feasible to record individual pathogen loads, and therefore true tolerance, on farm using routinely collected data. However, it may be estimated with group (farm) means, or other proxy measures. Although this results in a bias, this may still be useful for modeling and quantifying resistance and tolerance. We can then quantify success of selection, and this may enable us to decide whether to select for disease resistance versus disease tolerance. PMID:23248641

  19. Selection of pigs for improved coping with health and environmental challenges: breeding for resistance or tolerance?

    Directory of Open Access Journals (Sweden)

    Sarita Zhe Ying Guy

    2012-12-01

    Full Text Available The benefits of improved health and welfare in pigs have driven refinements in management and selection practices, one of which is the production of pig phenotypes that can maintain health and productivity by improving response against pathogens. Selection has traditionally been made for host resistance; but the alternative host defence mechanism – host tolerance – is now being considered, as breeding for disease tolerance allows maintenance of high performance across environments of increasing pathogenic load. A distinction must be made between these two mechanisms as they vary in their influence on host-pathogen interactions and pathogen evolution, and consequently on the results of breeding programmes. Many pig production studies have failed to distinguish between resistance and tolerance; although a distinction may not always be possible. This article reviews current perspectives in selective breeding for disease resistance and tolerance in growing pigs, and the attendant industry implications. To assess the viability of breeding for resistance and/or tolerance for improved response to disease and other environmental challenges, we propose the use of routine farm records, instead of data measurements taken from laboratory experiments. Consequently, a number of factors need to be taken into account simultaneously for a multidimensional modelling approach. This includes not only genotype and disease variables, but also descriptors of the environment, as well as any possible interactions. It may not be feasible to record individual pathogen loads, and therefore true tolerance, on farm using routinely collected data. However, it may be estimated with group (farm means, or other proxy measures. Although this results in a bias, this may still be useful for modelling and quantifying resistance and tolerance. We can then quantify success of selection, and this may enable us to decide whether to select for disease resistance versus disease

  20. The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping

    OpenAIRE

    Steve D M Brown; Moore, Mark W.

    2012-01-01

    Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse ...

  1. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    OpenAIRE

    Kohler, S.; Doelken, S.C.; Mungall, C.J.; Bauer, S.; Firth, H. V.; Bailleul-Forestier, I.; Black, G C M; Brown, D L; Brudno, M.; Campbell, J.; Fitzpatrick, D R; Eppig, J.T.; Jackson, A.P.; Freson, K.; Girdea, M.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with sev...

  2. Changes in nuclear phenotype frequencies following sequential cold shocks in Triatoma infestans (Hemiptera, Reduviidae

    Directory of Open Access Journals (Sweden)

    Silvana GP Campos

    2002-09-01

    Full Text Available The nuclear phenotypes of Malpighian tubule cells in fifth instar nymphs of Triatoma infestans, one of the most important vectors of Chagas disease, were studied following sequential shocks at 0ºC, separated by intervals of 8 h and 24 h at 30ºC, under conditions of moderate fasting and full nourishment. The insects pertained to colonies reared in the laboratory and originated from domestic specimens collected in the Brazilian states of São Paulo (north and Minas Gerais (south. Since nuclear phenotypes in this species are affected by single cold shocks, it was expected that these phenotypes could also be changed by sequential shocks. Nuclear phenotypes indicative of mechanisms of cell survival (nuclear fusion and heterochromatin decondensation and cell death (apoptosis and necrosis were observed concomitantly in all the conditions tested. Nuclear fusion and heterochromatin decondensation were not found relevant for the presumed acquisition of the cold-hardening response in T. infestans. The decreased frequency of apoptosis and necrosis following sequential cold shocks including under fasting conditions, indicated that tolerance to sequential cold shocks occurred in T. infestans of the mentioned origin.

  3. A model for generating several adaptive phenotypes from a single genetic event

    DEFF Research Database (Denmark)

    Møller, Henrik D; Andersen, Kaj S; Regenberg, Birgitte

    2013-01-01

    population against large fluctuations in size. Here we report that the general amino acid transporter Gap1 is a potential hub-switch. The GAP1 gene is flanked by two direct repeats that can lead to GAP1 deletions (∆gap1) and a self-replicating GAP1 circle. Thus, an isogenic GAP1 population can differentiate...... into two variant, reversible genotypes, ∆gap1 or GAP1 (circle). These subpopulations have different phenotypic advantages. A ∆gap1 population has a selective advantage on allantoin or ammonium as a nitrogen source and high stress tolerance. Advantages of the GAP1 population include amino acid uptake...

  4. Evaluation of the tolerance of acetic acid and 2-furaldehyde on the growth of Pichia stipitis and its respiratory deficient.

    Science.gov (United States)

    Ortiz-Muñiz, B; Rasgado-Mellado, J; Solis-Pacheco, J; Nolasco-Hipólito, C; Domínguez-González, J M; Aguilar-Uscanga, M G

    2014-10-01

    The use of lignocellulosic residues for ethanol production is limited by toxic compounds in fermenting yeasts present in diluted acid hydrolysates like acetic acid and 2-furaldehyde. The respiratory deficient phenotype gives the cell the ability to resist several toxic compounds. So the aim of this work was to evaluate the tolerance to toxic compounds present in lignocellulosic hydrolysates like acetic acid and 2-furaldehyde in Pichia stipitis and its respiratory deficient strains. The respiratory deficient phenotype was induced by exposure to chemical agents such as acriflavine, acrylamide and rhodamine; 23 strains were obtained. The selection criterion was based on increasing specific ethanol yield (g ethanol g(-1) biomass) with acetic acid and furaldehyde tolerance. The screening showed that P. stipitis NRRL Y-7124 ACL 2-1RD (lacking cytochrome c), obtained using acrylamide, presented the highest specific ethanol production rate (1.82 g g(-1 )h(-1)). Meanwhile, the ACF8-3RD strain showed the highest acetic acid tolerance (7.80 g L(-1)) and the RHO2-3RD strain was able to tolerate up to 1.5 g L(-1) 2-furaldehyde with a growth and ethanol production inhibition of 23 and 22 %, respectively. The use of respiratory deficient yeast phenotype is a strategy for ethanol production improvement in a medium with toxic compounds such as hydrolysed sugarcane bagasse amongst others. PMID:24700134

  5. Copper tolerance of Trichoderma species

    Directory of Open Access Journals (Sweden)

    Jovičić-Petrović Jelena

    2014-01-01

    Full Text Available Some Trichoderma strains can persist in ecosystems with high concentrations of heavy metals. The aim of this research was to examine the variability of Trichoderma strains isolated from different ecosystems, based on their morphological properties and restriction analysis of ITS fragments. The fungal growth was tested on potato dextrose agar, amended with Cu(II concentrations ranging from 0.25 to 10 mmol/l, in order to identify copper-resistant strains. The results indicate that some isolated strains of Trichoderma sp. show tolerance to higher copper concentrations. Further research to examine the ability of copper bioaccumulation by tolerant Trichoderma strains is needed. [Projekat Ministarstva nauke Republike Srbije, br. TR 31080 i br. III 43010

  6. Fault-tolerant Supervisory Control

    DEFF Research Database (Denmark)

    Izadi-Zamanabadi, Roozbeh

    systematic analysis of reconfiguration and design of supervisor logic. In addition, useful experience is obtained through implementation of a fault-tolerant control scheme against a simulated ship and its propulsion system. A development methodology, which was suggested in the Control Engineering Department...... realized on the basis of an extension to the traditional state-event machines. Due to parallelity (inherent modularity) the supervisor logic is more easily modified, updated, maintained, and tested. A salient feature is that a change in one task only necessitates redesign of essentially one corresponding...... state-event machine (SEM). A heuristic guideline is provided for designing the logic in form of SEMs. A ship propulsion system benchmark has been designed and used as a case study. This includes experimentation with the above methodologies and implementation of a fault-tolerant control against the...

  7. Fault Tolerant Wind Farm Control

    DEFF Research Database (Denmark)

    Odgaard, Peter Fogh; Stoustrup, Jakob

    2013-01-01

    with best at a wind turbine control level. However, some faults are better dealt with at the wind farm control level, if the wind turbine is located in a wind farm. In this paper a benchmark model for fault detection and isolation, and fault tolerant control of wind turbines implemented at the wind...... farm control level is presented. The benchmark model includes a small wind farm of nine wind turbines, based on simple models of the wind turbines as well as the wind and interactions between wind turbines in the wind farm. The model includes wind and power references scenarios as well as three...... relevant fault scenarios. This benchmark model is used in an international competition dealing with Wind Farm fault detection and isolation and fault tolerant control....

  8. Fault Tolerant External Memory Algorithms

    DEFF Research Database (Denmark)

    Jørgensen, Allan Grønlund; Brodal, Gerth Stølting; Mølhave, Thomas

    2009-01-01

    Algorithms dealing with massive data sets are usually designed for I/O-efficiency, often captured by the I/O model by Aggarwal and Vitter. Another aspect of dealing with massive data is how to deal with memory faults, e.g. captured by the adversary based faulty memory RAM by Finocchi and Italiano....... However, current fault tolerant algorithms do not scale beyond the internal memory. In this paper we investigate for the first time the connection between I/O-efficiency in the I/O model and fault tolerance in the faulty memory RAM, and we assume that both memory and disk are unreliable. We show a lower...... bound on the number of I/Os required for any deterministic dictionary that is resilient to memory faults. We design a static and a dynamic deterministic dictionary with optimal query performance as well as an optimal sorting algorithm and an optimal priority queue. Finally, we consider scenarios where...

  9. Rice's Salt Tolerance Gene Cloned

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    @@ In cooperation with US colleagues, CAS researchers have made significant progress in their studies into functional genes for key agronomic traits by cloning SKC1, a salt-tolerant functional gene of rice and making clear its biological functions and mechanisms. This pioneering work,which was reported in the Oct. issue of Nature Genetics (37:1141-1146), is believed to hold promise to increase the output of the crop plant in this country.

  10. Fault tolerance issues in nanoelectronics

    OpenAIRE

    Spagocci, S.

    2008-01-01

    The astonishing success story of microelectronics cannot go on indefinitely. In fact, once devices reach the few-atom scale (nanoelectronics), transient quantum effects are expected to impair their behaviour. Fault tolerant techniques will then be required. The aim of this thesis is to investigate the problem of transient errors in nanoelectronic devices. Transient error rates for a selection of nanoelectronic gates, based upon quantum cellular automata and single electron devi...

  11. SALT TOLERANCE OF CROP PLANTS

    Directory of Open Access Journals (Sweden)

    Hamdia, M. A

    2010-09-01

    Full Text Available Several environmental factors adversely affect plant growth and development and final yield performance of a crop. Drought, salinity, nutrient imbalances (including mineral toxicities and deficiencies and extremes of temperature are among the major environmental constraints to crop productivity worldwide. Development of crop plants with stress tolerance, however, requires, among others, knowledge of the physiological mechanisms and genetic controls of the contributing traits at different plant developmental stages. In the past 2 decades, biotechnology research has provided considerable insights into the mechanism of biotic stress tolerance in plants at the molecular level. Furthermore, different abiotic stress factors may provoke osmotic stress, oxidative stress and protein denaturation in plants, which lead to similar cellular adaptive responses such as accumulation of compatible solutes, induction of stress proteins, and acceleration of reactive oxygen species scavenging systems. Recently, the authores try to improve plant tolerance to salinity injury through either chemical treatments (plant hormones, minerals, amino acids, quaternary ammonium compounds, polyamines and vitamins or biofertilizers treatments (Asymbiotic nitrogen-fixing bacteria, symbiotic nitrogen-fixing bacteria and mycorrhiza or enhanced a process used naturally by plants to minimise the movement of Na+ to the shoot, using genetic modification to amplify the process, helping plants to do what they already do - but to do it much better."

  12. Tolerance bands for functional data.

    Science.gov (United States)

    Rathnayake, Lasitha N; Choudhary, Pankaj K

    2016-06-01

    Often the object of inference in biomedical applications is a range that brackets a given fraction of individual observations in a population. A classical estimate of this range for univariate measurements is a "tolerance interval." This article develops its natural extension for functional measurements, a "tolerance band," and proposes a methodology for constructing its pointwise and simultaneous versions that incorporates both sparse and dense functional data. Assuming that the measurements are observed with noise, the methodology uses functional principal component analysis in a mixed model framework to represent the measurements and employs bootstrapping to approximate the tolerance factors needed for the bands. The proposed bands also account for uncertainty in the principal components decomposition. Simulations show that the methodology has, generally, acceptable performance unless the data are quite sparse and unbalanced, in which case the bands may be somewhat liberal. The methodology is illustrated using two real datasets, a sparse dataset involving CD4 cell counts and a dense dataset involving core body temperatures. PMID:26574904

  13. Noise Tolerance under Risk Minimization

    CERN Document Server

    Manwani, Naresh

    2011-01-01

    In this paper we explore the problem of noise tolerant learning of classifiers. We formulate the problem as follows. We assume that there is an ${\\bf unobservable}$ training set which is noise-free. The actual training set given to the learning algorithm is obtained from this ideal data set by corrupting the class label of each example where the probability that the class label on an example is corrupted is a function of the feature vector of the example. This would account for almost all kinds of noisy data one may encounter in practice. We say that a learning method is noise tolerant if the classifiers learnt with the ideal noise-free data and with noisy data have the same classification accuracy on the noise-free data. In this paper we analyze the noise tolerant properties of risk minimization, which is a generic method for learning classifiers. We consider different loss functions such as 0-1 loss, hinge loss, exponential loss, squared error loss etc. We show that the risk minimization under 0-1 loss func...

  14. Soft Computing Approaches To Fault Tolerant Systems

    Directory of Open Access Journals (Sweden)

    Neeraj Prakash Srivastava

    2014-05-01

    Full Text Available We present in this paper as an introduction to soft computing techniques for fault tolerant systems and the terminology with different ways of achieving fault tolerance. The paper focuses on the problem of fault tolerance using soft computing techniques. The fundamentals of soft computing approaches and its type with introduction of fault tolerance are discussed. The main objective is to show how to implement soft computing approaches for fault detection, isolation and identification. The paper contains details about soft computing application with an application of wireless sensor network as fault tolerant system.

  15. Parallel fault-tolerant robot control

    Science.gov (United States)

    Hamilton, D. L.; Bennett, J. K.; Walker, I. D.

    1992-01-01

    A shared memory multiprocessor architecture is used to develop a parallel fault-tolerant robot controller. Several versions of the robot controller are developed and compared. A robot simulation is also developed for control observation. Comparison of a serial version of the controller and a parallel version without fault tolerance showed the speedup possible with the coarse-grained parallelism currently employed. The performance degradation due to the addition of processor fault tolerance was demonstrated by comparison of these controllers with their fault-tolerant versions. Comparison of the more fault-tolerant controller with the lower-level fault-tolerant controller showed how varying the amount of redundant data affects performance. The results demonstrate the trade-off between speed performance and processor fault tolerance.

  16. IRON-TOLERANT CYANOBACTERIA: IMPLICATIONS FOR ASTROBIOLOGY

    Science.gov (United States)

    Brown, Igor I.; Allen, Carlton C.; Mummey, Daniel L.; Sarkisova, Svetlana A.; McKay, David S.

    2006-01-01

    The review is dedicated to the new group of extremophiles - iron tolerant cyanobacteria. The authors have analyzed earlier published articles about the ecology of iron tolerant cyanobacteria and their diversity. It was concluded that contemporary iron depositing hot springs might be considered as relative analogs of Precambrian environment. The authors have concluded that the diversity of iron-tolerant cyanobacteria is understudied. The authors also analyzed published data about the physiological peculiarities of iron tolerant cyanobacteria. They made the conclusion that iron tolerant cyanobacteria may oxidize reduced iron through the photosystem of cyanobacteria. The involvement of both Reaction Centers 1 and 2 is also discussed. The conclusion that iron tolerant protocyanobacteria could be involved in banded iron formations generation is also proposed. The possible mechanism of the transition from an oxygenic photosynthesis to an oxygenic one is also discussed. In the final part of the review the authors consider the possible implications of iron tolerant cyanobacteria for astrobiology.

  17. Serum Biochemical Phenotypes in the Domestic Dog

    Science.gov (United States)

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  18. Invasion strategies in clonal aquatic plants: Are phenotypic differences caused by phenotypic plasticity or local adaptation?

    DEFF Research Database (Denmark)

    Riis, Tenna; Lambertini, Carla; Olesen, Birgit;

    2010-01-01

    . Methods: Field populations with a large phenotypic variety were sampled in a range of lakes and streams with different chemical and physical properties. The phenotypic plasticity of the species before and after cultivation was studied in a common garden growth experiment, and the genetic diversity of...

  19. Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype.

    Science.gov (United States)

    Bowron, Ann; Honeychurch, Julie; Williams, Maggie; Tsai-Goodman, Beverley; Clayton, Nicol; Jones, Lucy; Shortland, Graham J; Qureshi, Shakeel A; Heales, Simon J R; Steward, Colin G

    2015-03-01

    Barth syndrome (BTHS) is an X-linked disorder characterised by cardiac and skeletal myopathy, growth delay, neutropenia and 3-methylglutaconic aciduria (3-MGCA). Patients have TAZ gene mutations which affect metabolism of cardiolipin, resulting in low tetralinoleoyl cardiolipin (CL(4)), an increase in its precursor, monolysocardiolipin (MLCL), and an increased MLCL/CL(4) ratio. During development of a diagnostic service for BTHS, leukocyte CL(4) was measured in 156 controls and 34 patients with genetically confirmed BTHS. A sub-group of seven subjects from three unrelated families was identified with leukocyte CL(4) concentrations within the control range. This had led to initial false negative disease detection in two of these patients. MLCL/CL(4) in this subgroup was lower than in other BTHS patients but higher than controls, with no overlap between the groups. TAZ gene mutations in these families are all predicted to be pathological. This report describes the clinical histories of these seven individuals with an atypical phenotype: some features were typical of BTHS (five have had cardiomyopathy, one family has a history of male infant deaths, three have growth delay and five have 3-MGCA) but none has persistent neutropenia, five have excellent exercise tolerance and two adults are asymptomatic. This report also emphasises the importance of measurement of MLCL/CL(4) ratio rather than CL(4) alone in the biochemical diagnosis of the BTHS. PMID:25112388

  20. Key genes involved in desiccation tolerance and dormancy across life forms.

    Science.gov (United States)

    Costa, Maria Cecília D; Farrant, Jill M; Oliver, Melvin J; Ligterink, Wilco; Buitink, Julia; Hilhorst, Henk M W

    2016-10-01

    Desiccation tolerance (DT, the ability of certain organisms to survive severe dehydration) was a key trait in the evolution of life in terrestrial environments. Likely, the development of desiccation-tolerant life forms was accompanied by the acquisition of dormancy or a dormancy-like stage as a second powerful adaptation to cope with variations in the terrestrial environment. These naturally stress tolerant life forms may be a good source of genetic information to generate stress tolerant crops to face a future with predicted higher occurrence of drought. By mining for key genes and mechanisms related to DT and dormancy conserved across different species and life forms, unique candidate key genes may be identified. Here we identify several of these putative key genes, shared among multiple organisms, encoding for proteins involved in protection, growth and energy metabolism. Mutating a selection of these genes in the model plant Arabidopsis thaliana resulted in clear DT-, dormancy- and other seed-associated phenotypes, showing the efficiency and power of our approach and paves the way for the development of drought-stress tolerant crops. Our analysis supports a co-evolution of DT and dormancy by shared mechanisms that favour survival and adaptation to ever-changing environments with strong seasonal fluctuations. PMID:27593474