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Sent on Saturday, 2009 Jun 27Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: ChemMedChem. 2009 Jun 25. [Epub ahead of print]
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Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase.
Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH (UK), Fax: (+44) 1382 385542.
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP (1, 1-(1-benzo[b]thiophen-2-yl-cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (K(i)=1 muM) and biologically active against bloodstream T. brucei (EC(50)=10 muM), but with poor selectivity against mammalian MRC5 cells (EC(50)=29 muM). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.
PMID: 19557802 [PubMed - as supplied by publisher]
- 2: ChemMedChem. 2009 Jun 25. [Epub ahead of print]
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Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis.
Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland (UK), Fax: (+44) 1382-385-542.
Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (K(i)=330 nM) with an improved potency against T. brucei (EC(50)=775 nM).
PMID: 19557801 [PubMed - as supplied by publisher]
- 3: Mol Divers. 2009 Jun 26. [Epub ahead of print]
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Inhibitors of adenosine consuming parasites through polymer-assisted N-acylation of N(6)-substituted 5 (')-amino-5 (')-deoxyadenosines.
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
A series of 30 adenosine derivatives with three different substituents at the N(6)-position were prepared in order to evaluate their potential to inhibit the pathogenic protozoa Plasmodium falciparum and Trypanosoma brucei in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that N(6)-substitutents should increase stability against adenosine deaminases and allow the molecules to diffuse across parasite membranes. Starting from inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Three of the compounds displayed anti-plasmodial and one anti-trypanosomal activity in the single digit micromolar concentration range.
PMID: 19557536 [PubMed - as supplied by publisher]
- 4: PLoS Pathog. 2009 Jun;5(6):e1000494. Epub 2009 Jun 26.
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iNOS-Producing Inflammatory Dendritic Cells Constitute the Major Infected Cell Type during the Chronic Leishmania major Infection Phase of C57BL/6 Resistant Mice.
Laboratoire de Parasitologie, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium.
Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b(+) CD11c(+) Ly-6C(+) MHC-II(+) cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-gamma and MyD88 molecules with a partial contribution of TNF-alpha and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice.
PMID: 19557162 [PubMed - in process]
- 5: Am J Trop Med Hyg. 2009 Jul;81(1):52-4.
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Relapsing cutaneous leishmaniasis in a patient with ankylosing spondylitis treated with infliximab.
Medizinische Poliklinik, Divison of Infectious Diseases, University of Munich, Munich, Germany. matthias.mueller@med.uni-muenchen.de
A 31-year-old man with ankylosing spondylitis, receiving treatment with infliximab, presented with a large progressive cutaneous ulcer at the right knee. Biopsies showed Leishmania amastigotes, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis showed Leishmania infantum as the causative agent. After treatment with miltefosine, the ulcer resolved completely, and infliximab was reinstituted because of progression of spondylitis. After 1 year, there was a recurrent ulcer at the same site being positive for Leishmania DNA by PCR. Local treatment with sodium stibogluconate resulted in complete regression. Cutaneous leishmaniasis should be added to the list of opportunistic infections associated with anti-tumor necrosis factor (TNF) treatment. Despite recurrences, antileish-manial treatment may be effective in cases without alternatives to anti-TNF therapy.
PMID: 19556566 [PubMed - in process]
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- 6: Am J Trop Med Hyg. 2009 Jul;81(1):46-51.
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Is real-time polymerase chain reaction (PCR) more useful than a conventional PCR for the clinical management of leishmaniasis?
Department of Clinical Sciences L Sacco, section of Infectious Diseases and Immunopathology, University of Milan, Via GB Grassi 74, 20157 Milano, Italy. spinello.antinori@unimi.it
It is currently unknown if the use of a real-time polymerase chain reaction (PCR) adds value to the diagnosis and follow-up prognosis of patients affected by leishmaniasis. We performed a study using a real-time PCR directed against the alpha-polymerase gene and a semiquantitative PCR that target the SSU ribosomal RNA (rRNA) gene as control for the diagnosis and quantification of parasites in patients with visceral (VL) and cutaneous (CL) leishmaniasis. Our single copy real-time PCR missed one diagnosis of VL compared with the conventional PCR, whereas both PCR methods were able to detect Leishmania parasites in CL. Under anti-leishmania treatment the kinetics of parasitemia were comparable with the two methods. The real-time PCR directed against alpha-polymerase of Leishmania despite being able to make a more accurate quantification of parasites does not add to the decision-making management compared with a semiquantitative PCR, and it is comparatively expensive.
PMID: 19556565 [PubMed - in process]
- 7: Am J Trop Med Hyg. 2009 Jul;81(1):40-5.
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Visceral leishmaniasis in Tunisia: spatial distribution and association with climatic factors.
Laboratoire de Recherche 05SP03, Institut Pasteur de Tunis, Tunis, Tunisia.
Visceral leishmaniasis (VL) cases in children less than five years of age were recorded from 1996 through 2006 from Tunisian pediatric departments. Mean incidence rates were calculated for each of the 215 districts in the study area. Averages of annual rainfall and extreme values of low temperatures in winter and high temperatures in summer were used to characterize the climate of each district according to its continentality index and bioclimatic zone. A geographic information system and a local indicator of spatial association were used to summarize the spatial properties of VL distribution. Poisson spatial regression was performed to study the relationship between VL incidence rates and climatic parameters. We identified one hot-spot region of 35 inland districts located mostly in the semi-arid bioclimatic zone and two cold-spots located in coastal regions of the northeastern sub-humid zone and the southeastern arid zone. The incidence rate of VL was positively correlated with mean yearly rainfall and continentality index.
PMID: 19556564 [PubMed - in process]
- 8: Am J Trop Med Hyg. 2009 Jul;81(1):34-9.
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Risk factors for visceral leishmaniasis in a new epidemic site in Amhara Region, Ethiopia.
Malaria & Other Vector Borne Diseases, Prevention and Control Program, Ministry of Health, Addis Ababa, Ethiopia.
We conducted a case-control study to evaluate risk factors for visceral leishmaniasis during an epidemic in a previously unaffected district of Ethiopia. We also collected blood and bone marrow specimens from dogs in the outbreak villages. In multivariable analyses of 171 matched case-control pairs, dog ownership, sleeping under an acacia tree during the day, and habitually sleeping outside at night were associated with significantly increased risk. Specimens from 7 (3.8%) dogs were positive by immunofluorescent antibody test (IFAT) and both enzyme-linked immunosorbent assays (ELISAs), whereas Leishmania DNA was detected in 5 (2.8%) bone marrow aspirates (from 3 seropositive and 2 seronegative dogs). Insecticide-treated nets may only protect a portion of those at risk. Further research on the vectors, the role of the dog in the transmission cycle, and the effect of candidate interventions are needed to design the best strategy for control.
PMID: 19556563 [PubMed - in process]
- 9: Am J Trop Med Hyg. 2009 Jul;81(1):27-33.
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Comparative study of serologic tests for the diagnosis of asymptomatic visceral leishmaniasis in an endemic area.
Department of Tropical Medicine and Infectology, Federal University of Triângulo Mineiro, Uberaba, MG, Brazil.
Serologic tests have been widely used for the diagnosis of asymptomatic visceral leishmaniasis. This study evaluated five serologic tests used for the diagnosis of asymptomatic infection: enzyme-linked immunosorbent assay (ELISA) using promastigote antigen (ELISAp), ELISA using recombinant K39 (ELISA rK39), and K26 (ELISA rK26) antigens, an indirect immunofluorescence test using Leishmania (Leishmania) amazonensis promastigote antigen (IIFT), and an immunochromatographic test using rK39 antigen (TRALd). As a reference regarding the performance of the tests, patients with classic visceral leishmaniasis originating from Minas Gerais, Brazil (N = 36), were defined as the positive group and samples of healthy individuals from nonendemic areas (Argentina) (N = 127) were used as negative controls. Patients with other diseases such as cutaneous leishmaniasis (N = 53) and malaria (N = 56) were also studied to evaluate the chance of cross-reactivity in these tests. Finally, subjects from an area endemic for visceral leishmaniasis in Brazil (Porteirinha, northern Minas Gerais) (N = 1241) were screened for asymptomatic infection with Leishmania and Chagas disease. The sensitivity of the serologic tests was 50% (18/36), 66.7% (24/36), 69.4% (25/36), 83.3% (30/36), and 88.9% (32/36) for ELISAp, ELISA rK26, ELISA rK39, IIFT, and TRALd, respectively. Specificity, calculated using the truly negative group, was 96% (122/127) for TRALd, 97.6% (124/127) for ELISAp and IIFT, and 100% (127/127) for ELISA rK39 and rK26. Positivity in at least one test employing recombinant antigen was observed in 24 (45%) patients with cutaneous leishmaniasis and 47 (82.4%) with malaria. In the visceral leishmaniasis-endemic area, the positivity of the serologic tests ranged from 3.9% to 37.5%. The enzyme-linked immunosorbent assay (ELISA) tests using recombinant antigens were more frequently positive in subjects with a history of exposure to human or canine visceral leishmaniasis (ELISArK39: 14.6% [149/1017] versus 37.5% [84/224]; ELISA rK26: 12.7% [129/1017] versus 21.4% [48/224], P < 0.001 for both). Kappa agreement was low, with a maximum value of 0.449 between ELISAp and IIFT. In addition, among the 112 IIFT-positive subjects, 75 (67%) also presented positive serology for Chagas disease. In conclusion, IIFT and TRALd presented the best performance to diagnose classic cases of visceral leishmaniasis in an endemic area. Cross-reactivity of the tests with Chagas disease, cutaneous leishmaniasis, and malaria should be taken into account. However, the differences in the positivity of the tests used, together with the low agreement between results, do not permit to select the best test for the diagnosis of asymptomatic Leishmania infection.
PMID: 19556562 [PubMed - in process]
- 10: Science. 2009 Jun 26;324(5935):1644.
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- Comment on:
- Science. 2009 Apr 10;324(5924):265-8.
Sex in leishmania.
Department of Parasitology, Charles University in Prague, Prague 128 44, Czech Republic. volf@cesnet.cz
PMID: 19556486 [PubMed - in process]
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