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153. Metabolic and Target-Site Mechanisms Combine to Confer Strong DDT Resistance in Anopheles gambiae

Author

Mitchell, Sara N., primary, Rigden, Daniel J., additional, Dowd, Andrew J., additional, Lu, Fang, additional, Wilding, Craig S., additional, Weetman, David, additional, Dadzie, Samuel, additional, Jenkins, Adam M., additional, Regna, Kimberly, additional, Boko, Pelagie, additional, Djogbenou, Luc, additional, Muskavitch, Marc A. T., additional, Ranson, Hilary, additional, Paine, Mark J. I., additional, Mayans, Olga, additional, and Donnelly, Martin J., additional

Published
2014
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154. CYP6 P450 Enzymes and ACE-1 Duplication Produce Extreme and Multiple Insecticide Resistance in the Malaria Mosquito Anopheles gambiae

Author

Edi, Constant V., primary, Djogbénou, Luc, additional, Jenkins, Adam M., additional, Regna, Kimberly, additional, Muskavitch, Marc A. T., additional, Poupardin, Rodolphe, additional, Jones, Christopher M., additional, Essandoh, John, additional, Kétoh, Guillaume K., additional, Paine, Mark J. I., additional, Koudou, Benjamin G., additional, Donnelly, Martin J., additional, Ranson, Hilary, additional, and Weetman, David, additional

Published
2014
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155. Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

Author

Kalincik, Tomas, Spelman, Timothy, Trojano, Maria, Duquette, Pierre, Izquierdo, Guillermo, Grammond, Pierre, Lugaresi, Alessandra, Hupperts, Raymond, Cristiano, Edgardo, Van Pesch, Vincent, Grand'Maison, Francois, La Spitaleri, Daniele, Rio, Maria Edite, Flechter, Shlomo, Oreja-Guevara, Celia, Giuliani, Giorgio, Savino, Aldo, Amato, Maria Pia, Peterson, Thor, Fernandez-Bolanos, Ricardo, Bergamaschi, Roberto, Iuliano, Gerardo, Boz, Cavit, Lechner-Scott, Jeannette, Deri, Norma, Gray, Orla, Verheul, Freek, Fiol, Marcela, Barnett, Michael, van Munster, Erik, Santiago, Vetere, Moore, Fraser, Slee, Mark, Saladino, Maria Laura, Alroughani, Raed, Shaw, Cameron, Kasa, Krisztian, Petkovska-Boskova, Tatjana, den Braber-Moerland, Leontien, Chapman, Joab, Skromne, Eli, Herbert, Joseph, Peohlau, Dieter, Needham, Merrilee, Bacile, Elizabeth Alejandra, Oleschko Arruda, Walter, Paine, Mark, Singhal, Bhim, Vucic, Steve, Cabrera-Gomez, Jose Antonio, Butkueven, Helmut, Kalincik, Tomas, Spelman, Timothy, Trojano, Maria, Duquette, Pierre, Izquierdo, Guillermo, Grammond, Pierre, Lugaresi, Alessandra, Hupperts, Raymond, Cristiano, Edgardo, Van Pesch, Vincent, Grand'Maison, Francois, La Spitaleri, Daniele, Rio, Maria Edite, Flechter, Shlomo, Oreja-Guevara, Celia, Giuliani, Giorgio, Savino, Aldo, Amato, Maria Pia, Peterson, Thor, Fernandez-Bolanos, Ricardo, Bergamaschi, Roberto, Iuliano, Gerardo, Boz, Cavit, Lechner-Scott, Jeannette, Deri, Norma, Gray, Orla, Verheul, Freek, Fiol, Marcela, Barnett, Michael, van Munster, Erik, Santiago, Vetere, Moore, Fraser, Slee, Mark, Saladino, Maria Laura, Alroughani, Raed, Shaw, Cameron, Kasa, Krisztian, Petkovska-Boskova, Tatjana, den Braber-Moerland, Leontien, Chapman, Joab, Skromne, Eli, Herbert, Joseph, Peohlau, Dieter, Needham, Merrilee, Bacile, Elizabeth Alejandra, Oleschko Arruda, Walter, Paine, Mark, Singhal, Bhim, Vucic, Steve, Cabrera-Gomez, Jose Antonio, and Butkueven, Helmut

Abstract

To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from &ldquo

Published
2013

156. Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Author

van der Walt, Anneke, primary, Kolbe, Scott C., additional, Wang, Yejun E., additional, Klistorner, Alexander, additional, Shuey, Neil, additional, Ahmadi, Gelareh, additional, Paine, Mark, additional, Marriott, Mark, additional, Mitchell, Peter, additional, Egan, Gary F., additional, Butzkueven, Helmut, additional, and Kilpatrick, Trevor J., additional

Published
2013
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157. Pinpointing P450s associated with pyrethroid metabolism in the dengue vector, Aedes aegypti: developing new tools to combat insecticide resistance

Author

Stevenson, Bradley J., Pignatelli, Patricia, Nikou, Dimitra, Paine, Mark J. I., Stevenson, Bradley J., Pignatelli, Patricia, Nikou, Dimitra, and Paine, Mark J. I.

Abstract

BACKGROUND Pyrethroids are increasingly used to block the transmission of diseases spread by Aedes aegypti such as dengue and yellow fever. However, insecticide resistance poses a serious threat, thus there is an urgent need to identify the genes and proteins associated with pyrethroid resistance in order to produce effective counter measures. In Ae. aegypti, overexpression of P450s such as the CYP9J32 gene have been linked with pyrethroid resistance. Our aim was to confirm the role of CYP9J32 and other P450s in insecticide metabolism in order to identify potential diagnostic resistance markers. METHODOLOGY/PRINCIPAL FINDINGS We have expressed CYP9J32 in Escherichia coli and show that the enzyme can metabolize the pyrethroids permethrin and deltamethrin. In addition, three other Ae. aegypti P450s (CYP9J24, CYP9J26, CYP9J28) were found capable of pyrethroid metabolism, albeit with lower activity. Both Ae. aegypti and Anopheles gambiae P450s (CYP's 6M2, 6Z2, 6P3) were screened against fluorogenic and luminescent substrates to identify potential diagnostic probes for P450 activity. Luciferin-PPXE was preferentially metabolised by the three major pyrethroid metabolisers (CYP9J32, CYP6M2 and CYP6P3), identifying a potential diagnostic substrate for these P450s. CONCLUSIONS/SIGNIFICANCE P450s have been identified with the potential to confer pyrethroid resistance in Ae.aegypti. It is recommended that over expression of these enzymes should be monitored as indicators of resistance where pyrethroids are used.

Published
2012

158. Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from Ghana

Author

Mitchell, Sarah N., Stevenson, Bradley, Muller, Pie, Wilding, Craig S., Egyir-Yawson, Alexander, Field, Stuart G., Hemingway, Janet, Paine, Mark J. I., Ranson, Hilary, Donnelly, Martin James, Mitchell, Sarah N., Stevenson, Bradley, Muller, Pie, Wilding, Craig S., Egyir-Yawson, Alexander, Field, Stuart G., Hemingway, Janet, Paine, Mark J. I., Ranson, Hilary, and Donnelly, Martin James

Abstract

In the last decade there have been marked reductions in malaria incidence in sub-Saharan Africa. Sustaining these reductions will rely upon insecticides to control the mosquito malaria vectors. We report that in the primary African malaria vector, Anopheles gambiae sensu stricto, a single enzyme, CYP6M2, confers resistance to two classes of insecticide. This is unique evidence in a disease vector of cross-resistance associated with a single metabolic gene that simultaneously reduces the efficacy of two of the four classes of insecticide routinely used for malaria control. The gene-expression profile of a highly DDT-resistant population of A. gambiae s.s. from Ghana was characterized using a uniquewhole-genome microarray. A number of genes were significantly overexpressed compared with two susceptible West African colonies, including genes from metabolic families previously linked to insecticide resistance. One of the most significantly overexpressed probe groups (false-discovery rate-adjusted P < 0.0001) belonged to the cytochrome P450 gene CYP6M2. This gene is associated with pyrethroid resistance in wild A. gambiae s.s. populations) and can metabolize both type I and type II pyrethroids in recombinant protein assays. Using in vitro assays we show that recombinant CYP6M2 is also capable of metabolizing the organochlorine insecticide DDT in the presence of solubilizing factor sodium cholate.

Published
2012

159. Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

Author

Stevenson, Bradley, Bibby, Jaclyn, Pignatelli, Patricia, Muangnoicharoen, Sant, O'Neill, Paul M., Lian, Lu-Yun, Muller, Pie, Nikou, Dimitra, Steven, Andrew, Hemingway, Janet, Sutcliffe, Michael J., Paine, Mark J. I., Stevenson, Bradley, Bibby, Jaclyn, Pignatelli, Patricia, Muangnoicharoen, Sant, O'Neill, Paul M., Lian, Lu-Yun, Muller, Pie, Nikou, Dimitra, Steven, Andrew, Hemingway, Janet, Sutcliffe, Michael J., and Paine, Mark J. I.

Published
2011

160. The Multiple Sclerosis Severity Score re-examined: Expanded Disability Status Scale rank stability in the MSBase dataset increases five years after onset of multiple sclerosis

Author

UCL - (SLuc) Service de neurologie, UCL - Cliniques universitaires Saint-Luc, UCL, Butzkueven, Helmut, Van Pesch, Vincent, Jolley, Damien, Trojano, Maria, Zwanikken, Cees, Maison, Francois Grand, Duquette, Pierre, Grammond, Pierre, Bergamaschi, Roberto, Giuliani, Giorgio, Timmermans, Bertine, Boz, Cavit, Rio, Maria Edite, Petersen, Thor, Poehlau, Dieter, Cristiatio, Edgardo, Lechner-Scott, Jeannette, Fiol, Marcela, Arruda, Walter Oleschko, Izquierdo, Guillernio, Flechter, Shlomo, Paine, Mark, Deri, Norma, Savino, Aldo, Cabrera-Gomez, Jose Antonio, 13th Annnual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis, UCL - (SLuc) Service de neurologie, UCL - Cliniques universitaires Saint-Luc, UCL, Butzkueven, Helmut, Van Pesch, Vincent, Jolley, Damien, Trojano, Maria, Zwanikken, Cees, Maison, Francois Grand, Duquette, Pierre, Grammond, Pierre, Bergamaschi, Roberto, Giuliani, Giorgio, Timmermans, Bertine, Boz, Cavit, Rio, Maria Edite, Petersen, Thor, Poehlau, Dieter, Cristiatio, Edgardo, Lechner-Scott, Jeannette, Fiol, Marcela, Arruda, Walter Oleschko, Izquierdo, Guillernio, Flechter, Shlomo, Paine, Mark, Deri, Norma, Savino, Aldo, Cabrera-Gomez, Jose Antonio, and 13th Annnual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis

Published
2008

161. Field-caught permethrin-resistant anopheles gambiae overexpress CYP6P3, a P450 that metabolises pyrethroids

Author

Müller, Pie, Warr, Emma, Stevenson, Bradley J., Pignatelli, Patricia M., Morgan, John C., Steven, Andrew, Yawson, Alexander E., Mitchell, Sara N., Ranson, Hilary, Hemingway, Janet, Paine, Mark J. I., Donnelly, Martin J., Müller, Pie, Warr, Emma, Stevenson, Bradley J., Pignatelli, Patricia M., Morgan, John C., Steven, Andrew, Yawson, Alexander E., Mitchell, Sara N., Ranson, Hilary, Hemingway, Janet, Paine, Mark J. I., and Donnelly, Martin J.

Abstract

Insects exposed to pesticides undergo strong natural selection and have developed various adaptive mechanisms to survive. Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is receiving increasing attention because it threatens the sustainability of malaria vector control programs in sub-Saharan Africa. An understanding of the molecular mechanisms conferring pyrethroid resistance gives insight into the processes of evolution of adaptive traits and facilitates the development of simple monitoring tools and novel strategies to restore the efficacy of insecticides. For this purpose, it is essential to understand which mechanisms are important in wild mosquitoes. Here, our aim was to identify enzymes that may be important in metabolic resistance to pyrethroids by measuring gene expression for over 250 genes potentially involved in metabolic resistance in phenotyped individuals from a highly resistant, wild A. gambiae population from Ghana. A cytochrome P450, CYP6P3, was significantly overexpressed in the survivors, and we show that the translated enzyme metabolises both alpha-cyano and non-alpha-cyano pyrethroids. This is the first study to demonstrate the capacity of a P450 identified in wild A. gambiae to metabolise insecticides. The findings add to the understanding of the genetic basis of insecticide resistance in wild mosquito populations.

Published
2008

162. The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling

Author

Chandor-Proust, Alexia, primary, Bibby, Jaclyn, additional, Régent-Kloeckner, Myriam, additional, Roux, Jessica, additional, Guittard-Crilat, Emilie, additional, Poupardin, Rodolphe, additional, Riaz, Muhammad Asam, additional, Paine, Mark, additional, Dauphin-Villemant, Chantal, additional, Reynaud, Stéphane, additional, and David, Jean-Philippe, additional

Published
2013
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172. Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

Author

Stevenson, Bradley J., primary, Bibby, Jaclyn, additional, Pignatelli, Patricia, additional, Muangnoicharoen, Sant, additional, O’Neill, Paul M., additional, Lian, Lu-Yun, additional, Müller, Pie, additional, Nikou, Dimitra, additional, Steven, Andrew, additional, Hemingway, Janet, additional, Sutcliffe, Michael J., additional, and Paine, Mark J.I., additional

Published
2011
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180. A micro-fabricated colloid microthruster : high voltage electrostatic fields on a MEMS device

Author

Paine, Mark Daniel. and Paine, Mark Daniel.

Abstract

In recent years, there has been a resurgence of interest in colloid propulsion, sparked by a newly increased understanding of the underlying electrospray process. Electrospray produces sprays of charged droplets with an efficiency and specific charge that makes colloid propulsion very attractive. Traditionally colloid thrusters use hollow metal needles from which the spray is extracted using a nearby high-voltage electrode. However, this is a very problematic approach when mass is restricted, and lacks the dimensional consistency that is required across an array. The research reported here has produced a colloid microthruster, using micro-fabrication techniques, which aims to solve those problems and enable colloid propulsion as a microthrust technology with a novel approach to thrust throttling. Large arrays of electrospray nozzles were fabricated out of silicon. The amount of fuel lost by evaporation is drastically cut because the nozzles have very small exit diameters. A new packaging system delivers fuel to the nozzles at a prescribed pressure so the liquid remains at the exit, even at high vacuum. Extraction electrodes are situated on-chip; a silicon dioxide layer insulates them from the substrate. The electrodes are fundamental to the electrospray operation and this work is the first in which they are integrated with microfabricated nozzles. The approach benefits greatly from batch processing and the reduced dimensions mean significantly lower voltages are required. The design must create and withstand extremely high electrical fields produced by kV voltages. To ascertain the suitability of the design I tested the electrode systems and determined the major factors contributing to electrical breakdown. The breakdown strength and destructive mechanism have been discovered for differing geometries and oxide thickness, over a range of experimental conditions that simulate the predicted operational environment.

Published
2002

184. Field-Caught Permethrin-Resistant Anopheles gambiae Overexpress CYP6P3, a P450 That Metabolises Pyrethroids

Author

Müller, Pie, primary, Warr, Emma, additional, Stevenson, Bradley J., additional, Pignatelli, Patricia M., additional, Morgan, John C., additional, Steven, Andrew, additional, Yawson, Alexander E., additional, Mitchell, Sara N., additional, Ranson, Hilary, additional, Hemingway, Janet, additional, Paine, Mark J. I., additional, and Donnelly, Martin J., additional

Published
2008
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197. DDT-based indoor residual spraying suboptimal for visceral leishmaniasis elimination in India.

Author

Coleman, Michael, Foster, Geraldine M., Deb, Rinki, Pratap Singh, Rudra, Ismail, Hanafy M., Shivam, Pushkar, Kumar Ghosh, Ayan, Dunkley, Sophie, Kumar, Vijay, Coleman, Marlize, Hemingway, Janet, Paine, Mark J. I., and Das, Pradeep

Subjects
DDT (Insecticide), VISCERAL leishmaniasis, QUALITY assurance, DELTAMETHRIN, PYRETHROIDS
Abstract

Indoor residual spraying (IRS) is used to control visceral leishmaniasis (VL) in India, but it is poorly quality assured. Quality assurance was performed in eight VL endemic districts in Bihar State, India, in 2014. Residual dichlorodiphenyltrichloroethane (DDT) was sampled from walls using Bostik tape discs, and DDT concentrations [grams of active ingredient per square meter (g ai/m²)] were determined using HPLC. Pre-IRS surveys were performed in three districts, and post-IRS surveys were performed in eight districts. A 20% threshold above and below the target spray of 1.0 g ai/m² was defined as "in range." The entomological assessments were made in four districts in IRS and non- IRS villages. Vector densities were measured: pre-IRS and 1 and 3 mo post-IRS. Insecticide susceptibility to 4% DDT and 0.05% deltamethrin WHO-impregnated papers was determined with wild-caught sand flies. The majority (329 of 360, 91.3%) of pre-IRS samples had residual DDT concentrations of <0.1 g ai/m². The mean residual concentration of DDT post-IRS was 0.37 g ai/m²; 84.9% of walls were undersprayed, 7.4% were sprayed in range, and 7.6% were oversprayed. The abundance of sand flies in IRS and non-IRS villages was significantly different at 1 mo post-IRS only. Sand flies were highly resistant to DDT but susceptible to deltamethrin. The Stockholm Convention, ratified by India in 2006, calls for the complete phasing out of DDT as soon as practical, with limited use in the interim where no viable IRS alternatives exist. Given the poor quality of the DDT-based IRS, ready availability of pyrethroids, and susceptibility profile of Indian sand flies, the continued use of DDT in this IRS program is questionable. [ABSTRACT FROM AUTHOR]

Published
2015
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198. Up-regulation of silent information regulator 2 (Sir2) is associated with amphotericin B resistance in clinical isolates of Leishmania donovani.

Author

Purkait, Bidyut, Singh, Ruby, Wasnik, Kirti, Das, Sushmita, Kumar, Ashish, Paine, Mark, Dikhit, Manas, Singh, Dharmendra, Sardar, Abul H., Ghosh, Ayan K., and Das, Pradeep

Subjects
SIRTUINS, LEISHMANIA donovani, AMPHOTERICIN B, DRUG resistance, NAD (Coenzyme), DEACETYLATION, REACTIVE oxygen species, APOPTOSIS, PROTOZOA
Abstract

Objective: Silent information regulator 2 (Sir2) is involved in parasite survival and apoptosis. Here, we aimed to explore the involvement of Sir2 in amphotericin B (AmB) resistance mechanism in Leishmania donovani. Methods: The expression levels of Sir2, MDR1 and NAD+ biosynthetic pathway enzymes in AmB-resistant and -susceptible parasites were measured and total intracellular NAD+/NADH ratios were compared. Overexpression and knockout constructs of Sir2 were transfected in AmB-resistant and -susceptible parasites. Both resistant and susceptible parasites were inhibited with sirtinol for 4 h. The deacetylase activity of Sir2, the expression level of MDR1, the rate of AmB efflux, concentrations of reactive oxygen species (ROS) and levels of apoptosis were examined in WT, inhibited and transfected parasites, and the AmB susceptibility of the respective parasites was measured by determining the LD50 of AmB. Results: Levels of mRNA, protein and NAD+-dependent deacetylase activity of Sir2 were elevated in resistant versus susceptible parasites. Inhibition and/or deletion of Sir2 allele showed a decreased mRNA level of MDR1, lower drug efflux, increased ROS concentration, apoptosis-like phenomenon and decreased LD50 of AmB in resistant parasites. In contrast, Sir2 overexpression in susceptible parasites reversed drug susceptibility producing a resistant phenotype. This was associated with increased LD50 of AmB along with increased expression levels of MDR1, drug efflux and reduced concentrations of ROS, corresponding to decreased apoptosis of resistant to WT sensitive. Conclusions: Sir2 plays a critical role in AmB resistance by regulating MDR1, ROS concentration and apoptosis-like phenomena and may be a new resistance marker for visceral leishmaniasis. [ABSTRACT FROM AUTHOR]

Published
2015
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200. Acute Lead Toxicosis in Mourning Doves

Author

SCHULZ, JOHN H., primary, MILLSPAUGH, JOSHUA J., additional, BERMUDEZ, ALEX J., additional, GAO, XIAOMING, additional, BONNOT, THOMAS W., additional, BRITT, LISA G., additional, and PAINE, MARK, additional

Published
2006
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