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Sent on Wednesday, 2011 Mar 16Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results |
1. | Antimicrob Agents Chemother. 2011 Mar 14. [Epub ahead of print]Trypanocidal furamidine analogues: influence of pyridine nitrogens on trypanocidal activity, transport kinetics and resistance patterns.Ward CP, Wong PE, Burchmore RJ, de Koning HP, Barrett MP.Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow; Henry Wellcome Functional Genomics Facility, Joseph Black Building, University of Glasgow. AbstractCurrent therapies for Human African trypanosomiasis (HAT) are unsatisfactory and under threat from emerging drug resistance linked to the loss of transporters e.g. the P2 aminopurine transporter (TbAT1). Here we compare the uptake and trypanocidal properties of furamidine (DB75), recently evaluated in clinical trials against stage 1 (haemolymphatic) HAT, and two aza analogues, DB820 and CPD0801 (DB829) which are candidate compounds against stage 2 (neurological) disease. IC50 values determined in vitro were sub-micromolar against both wild-type and transporter mutant parasites, with DB75 displaying better and DB820 similar trypanotoxicity compared to the widely used veterinary trypanocide diminazene, while CPD0801 was less active. Activity correlated with uptake and with minimum drug exposure time necessary to commit trypanosomes to death: DB75 accumulated at double and ten-fold the rate of DB820 and CPD0801 respectively. All three compounds inhibited P2-mediated adenosine transport with similar Ki values, indicating affinity for this permease in the low to sub micromolar range. Uptake of DB75, DB820 and CPD0801 was significantly reduced in tbat1(-/-) parasites and was sensitive to inhibition by adenine, showing that all three compounds are substrates for the P2 transporter. Uptake was significantly less in vitro compared to parasites freshly isolated from infected rats, correlating with a down-regulation of P2 activity in vitro. We conclude that DB75, DB820 and CPD0801 are actively accumulated by T. b. brucei with P2 as the main transport route. The aza analogues of DB75 accumulate more slowly than furamidine itself and reveal less trypanocidal activity in standard in vitro drug sensitivity assays. |
PMID: 21402852 [PubMed - as supplied by publisher] | |
2. | J Neuroimmunol. 2011 Mar 12. [Epub ahead of print]Interleukin-13 reduces hyperalgesia and the level of interleukin-1β in BALB/c mice infected with Leishmania major with an up-regulation of interleukin-6.K aram MC, Al-Kouba JE, Bazzi SI, Smith CB, Leung L.Faculty of Sciences, Department of Biology, University of Balamand, Al-Kurah, Lebanon. AbstractThe anti-inflammatory cytokines interleukin-10 (IL-10) and interleukin-13 (IL-13) were shown to reduce hyperalgesia in some models such as rats exposed to UV rays. In addition, IL-10 was also shown to reduce hyperalgesia in high dose of Leishmania major-induced inflammation in BALB/c mice accompanied by a significant decrease in the levels of interleukin-1β (IL-1β) in the paws of infected mice, while no effect on the levels of IL-6 was observed. In this study, we injected BALB/c mice with a high dose of L. major and treated them with IL-13 (15ng/animal) for twelve days (excluding the weekends) and hyperalgesia was assessed using thermal pain tests. Furthermore, the levels of IL-1β and IL-6 were also assessed at different post-infection days. Our results show that IL-6 and more importantly IL-1β don't play a direct role in the L. major-induced hyperalgesia and that IL-13 induces this hyperalgesia through the down-regulation of IL-1β and another proinflammatory cytokine (most probably TNF-α). Furthermore, our data show that IL-13 leads to the upregulation of the level IL-6 which initially seems to have no direct role in the induced hyperalgesia. Therefore, we suggest that the L. major-induced hyperalgesia is mainly mediated by the cytokine cascade leading to the production of sympathetic amines. Copyright © 2011 Elsevier B.V. All rights reserved. |
PMID: 21402416 [PubMed - as supplied by publisher] | |
3. | J Eukaryot Microbiol. 2011 Mar 14. doi: 10.1111/j.1550-7408.2011.00539.x. [Epub ahead of print]Kinetoplast Morphology and Segregation Pattern as a Marker for Cell Cycle Progression in Leishmania donovani(1).Minocha N, Kumar D, Rajanala K, Saha S.Department of Microbiology, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India, and National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. AbstractTrypanosomatids are typified by uniquely configured mitochondrial DNA-the kinetoplast. The replication timing of kinetoplast DNA (kDNA) is closely linked to nuclear S phase, but nuclear and kinetoplast compartments display staggered timing of segregation, post-replication. Kinetoplast division is completed before nuclear division in Trypanosoma species while nuclear division is completed first in Crithidia species. Leishmania donovani is the causative agent of visceral leishmaniasis, a form of leishmanial infection that is often fatal. Cell cycle related studies in Leishmania are hampered by difficulties in synchronizing these cells. This report examines the replication/segregation pattern and morphology of the kinetoplast in L. donovani with the aim of determining if these traits can be used to assign cell cycle stage to individual cells. By labeling replicating cells with bromodeoxyuridine after synchronization with hydroxyurea, we find that although both nuclear and kDNA initiate replication in early S phase, nuclear division precedes kinetoplast segregation in 80% of the cells. The kinetoplast is roundish/short rod-like in G1 and in early to mid-S phase, but prominently elongated/bilobed in late S phase and early G2/M. These morphological traits and segregation pattern of the kinetoplast can be used as a marker for cell cycle stage in a population of asynchronously growing L. donovani promastigotes, in place of cell synchronization procedures or instead of using antibody staining for cell cycle stage marker proteins. © 2011 The Author(s). Journal of Eukaryotic Microbiology © 2011 International Society of Protistologists. |
PMID: 21401783 [PubMed - as supplied by publisher] | |
4. | Curr Top Med Chem. 2011 Mar 14. [Epub ahead of print]State of the Art in African Trypanosome Drug Discovery.Jacobs RT, Nare B, Phillips MA.SCYNEXIS, Inc., Research Triangle Park, North Carolina 27709-2878, USA. margaret.phillips@UTSouthwestern.edu. AbstractAfrican sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer. This breakthrough represents the only new therapy for HAT since the approval of eflornithine. A number of research programs are on going to exploit the unusual biochemical pathways in the parasite to identify new targets for target based drug discovery programs. HTS efforts are also underway to discover new chemical entities through whole organism screening approaches. A number of inhibitors with anti-trypanosomal activity have been identified by both approaches, but none of the programs are yet at the stage of identifying a preclinical candidate. This dire situation underscores the need for continued effort to identify new chemical agents for the treatment of HAT. |
PMID: 21401507 [PubMed - as supplied by publisher] | |
5. | Curr Top Med Chem. 2011 Mar 14. [Epub ahead of print]Finding New Hits in Neglected Disease Projects: Target or Phenotypic Based Screening?Gilbert IH, Leroy D, Frearson JA.Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, DD1 5EH, UK. i.h.gilbert@dundee.ac.uk. AbstractIn this article, we discuss the merits of both target-based and phenotypic screening strategies to find starting points for drug discovery projects in neglected tropical disease including: human African trypanosomiasis, Chagas disease, leishmaniasis and malaria. Techological advances now mean that it is possible to undertake high quality screens against isolated molecular targets at considerable scale. However target selection is a minefield of potential issues and often molecules identified and developed as potent inhibitors of targets do not translate into actives against the whole parasite. The potential for rapid resistance development is also a key issue when tackling individual molecular targets. In phenotypic screening, compounds are screened against the whole organism, looking for activity without apriori knowledge of the target(s) being modulated. This approach brings the benefits of increased chances of efficacy and potentially slowed resistance development of a successful medicine but the lack of knowledge of the molecular target can make the optimisation process more challenging. Advances in screening technologies has now brought phenotypic approaches up to the scale attained by target-based approaches and we discuss opportunities for advances in this arena concluding that a robust drug discovery portfolio for such diseases should include both phenotypic and target-based approaches. |
PMID: 21401505 [PubMed - as supplied by publisher] | |
6. | Rev Argent Microbiol. 2010 Oct-Dec;42(4):316.[Giemsa stain in the differential diagnosis of infectious diseases with cutaneous involvement].[Article in Spanish] Arechavala AI, Bianchi MH, Santiso GM, Lehmann EA, Walker L, Negroni R.Unidad Micología, Hospital de Infecciosas F. J. Muñiz, Uspallata CABA, Argentina. micologia@intramed.net Free Article |
PMID: 21229205 [PubMed - indexed for MEDLINE] | |
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7. | Med Sci (Paris). 2010 Dec;26(12):1025-7.[Mobile elements jump between parasites and vertebrate hosts].[Article in French] Gilbert C, Schaack S, Feschotte C. |
PMID: 21187035 [PubMed - indexed for MEDLINE] | |
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8. | PLoS Negl Trop Dis. 2010 Dec 14;4(12):e916.The potential economic value of a Trypanosoma cruzi (Chagas disease) vaccine in Latin America.Lee BY, Bacon KM, Connor DL, Willig AM, Bailey RR.Public Health Computational and Operations Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. BYL1@pitt.edu AbstractBACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), is the leading etiology of non-ischemic heart disease worldwide, with Latin America bearing the majority of the burden. This substantial burden and the limitations of current interventions have motivated efforts to develop a vaccine against T. cruzi. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a decision analytic Markov computer simulation model to assess the potential economic value of a T. cruzi vaccine in Latin America from the societal perspective. Each simulation run calculated the incremental cost-effectiveness ratio (ICER), or the cost per disability-adjusted life year (DALY) avoided, of vaccination. Sensitivity analyses evaluated the impact of varying key model parameters such as vaccine cost (range: $0.50-$200), vaccine efficacy (range: 25%-75%), the cost of acute-phase drug treatment (range: $10-$150 to account for variations in acute-phase treatment regimens), and risk of infection (range: 1%-20%). Additional analyses determined the incremental cost of vaccinating an individual and the cost per averted congestive heart failure case. Vaccination was considered highly cost-effective when the ICER was ≤1 times the GDP/capita, still cost-effective when the ICER was between 1 and 3 times the GDP/capita, and not cost-effective when the ICER was >3 times the GDP/capita. Our results showed vaccination to be very cost-effective and often economically dominant (i.e., saving costs as well providing health benefits) for a wide range of scenarios, e.g., even when risk of infection was as low as 1% and vaccine efficacy was as low as 25%. Vaccinating an individual could likely provide net cost savings that rise substantially as risk of infection or vaccine efficacy increase. CONCLUSIONS/SIGNIFICANCE: Results indicate that a T. cruzi vaccine could provide substantial economic benefit, depending on the cost of the vaccine, and support continued efforts to develop a human vaccine. |
PMID: 21179503 [PubMed - indexed for MEDLINE] | |
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9. | Diagn Microbiol Infect Dis. 2011 Jan;69(1):74-81.Evaluation of the Abbott ARCHITECT Chagas prototype assay.Praast G, Herzogenrath J, Bernhardt S, Christ H, Sickinger E.Abbott GmbH & Co. KG, Wiesbaden-Delkenheim, Germany. gerald.praast@abbott.com AbstractSerologic tests are established tools for the diagnosis of Chagas disease applied to support a safe blood supply in endemic countries. However, sensitivity and specificity of most commercially available enzyme-linked immunosorbent assays (ELISAs) are not regarded as adequate enough to rely on a single assay to determine the Trypanosoma cruzi infection status of a blood donor or a patient. The overall assay performance is driven by the general choice of antigens and the actual antigen cocktail provided in the test. In this report we describe key performance data of the Abbott ARCHITECT Chagas prototype assay in comparison to the well-recognized bioMérieux ELISA cruzi assay. The ARCHITECT assay demonstrated superior specificity (99.99% versus 99.93%) and sensitivity (99.85% versus 98.38%), along with excellent precision, thus showing the potential to serve as single assay to determine the T. cruzi status of a given blood unit or diagnostic specimen on a fully automated instrument platform. Copyright © 2011 Elsevier Inc. All rights reserved. |
PMID: 21146717 [PubMed - indexed for MEDLINE] | |
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10. | Enferm Infecc Microbiol Clin. 2010 Dec;28(10):751-2. Epub 2010 Jun 26.Co-infection with two emergent old pathogens: Trypanosoma cruzi and Helicobacter pylori.Pinazo MJ, Ignacio Elizalde J, de Jesús Posada E, Gascón J. |
PMID: 20580134 [PubMed - indexed for MEDLINE] | |
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