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Sent on Friday, 2011 Jun 03Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Genes Immun. 2011 Jun 2. [Epub ahead of print]FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil.Castellucci L, Jamieson SE, Miller EN, de Almeida LF, Oliveira J, Magalhães A, Guimarães LH, Lessa M, Lago E, de Jesus AR, Carvalho EM, Blackwell JM.Source1] Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Federal University of Bahia, Salvador, Brazil [2] Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK. AbstractMapping murine genes controlling cutaneous leishmaniasis (CL) identified Fli1 as a candidate influencing resistance to L. major and enhanced wound healing. We examine FLI1 as a gene controlling CL and mucosal leishmaniasis (ML) caused by L. braziliensis in humans. Intron 1 single nucleotide polymorphisms tagging promoter and enhancer elements were analysed in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Robust case-pseudocontrol logistic regression analysis showed association between allele C (odds ratio (OR) 1.65; 95% confidence interval 1.18-2.29; P=0.003) of FLI1_rs7930515 and CL in the primary sample that was confirmed (OR 1.60; 95% confidence interval 1.10-2.33; P=0.014) in the replication set (combined P=1.8 × 10(-4)). FLI1_rs7930515 is in linkage disequilibrium with the functional GAn microsatellite in the proximal promoter. Haplotype associations extended across the enhancer, which was not polymorphic. ML associated with inverse haplotypes compared with CL. Wound healing is therefore important in CL, providing potential for therapies modulating FLI1.Genes and Immunity advance online publication, 2 June 2011; doi:10.1038/gene.2011.37. |
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| 2. | Am J Trop Med Hyg. 2011 Jun;84(6):913-922.Phylogenetics of the Phlebotomine Sand Fly Group Verrucarum (Diptera: Psychodidae: Lutzomyia).Cohnstaedt LW, Beati L, Caceres AG, Ferro C, Munstermann LE.SourceArthropod-Borne Animal Disease Research Unit, Center for Grain and Animal Health Research, Agricultural Research Service, United States Department of Agriculture, Manhattan, Kansas; Georgia Southern University, Institute of Arthropodology and Parasitology, Statesboro, Georgia; Departmento Académico de Microbiologia Médica, Facultad de Medicina Humana, Universidad Nacional, Mayor de San Marcos, Lima, Peru; Laboratorio de Entomología, Instituto Nacional de Salud, Avenida Calle 26 No 51-60, Bogotá, Colombia; Instituto Nacional de Salud, Bogotá, Colombia; Yale School of Public Health, Yale University, New Haven, Connecticut. AbstractAbstract. Within the sand fly genus Lutzomyia, the Verrucarum species group contains several of the principal vectors of American cutaneous leishmaniasis and human bartonellosis in the Andean region of South America. The group encompasses 40 species for which the taxonomic status, phylogenetic relationships, and role of each species in disease transmission remain unresolved. Mitochondrial cytochrome c oxidase I (COI) phylogenetic analysis of a 667-bp fragment supported the morphological classification of the Verrucarum group into series. Genetic sequences from seven species were grouped in well-supported monophyletic lineages. Four species, however, clustered in two paraphyletic lineages that indicate conspecificity-the Lutzomyia longiflocosa-Lutzomyia sauroida pair and the Lutzomyia quasitownsendi-Lutzomyia torvida pair. COI sequences were also evaluated as a taxonomic tool based on interspecific genetic variability within the Verrucarum group and the intraspecific variability of one of its members, Lutzomyia verrucarum, across its known distribution. |
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| 3. | Am J Trop Med Hyg. 2011 Jun;84(6):906-12.Disseminated Cutaneous Leishmaniasis Resembling Post-Kala-Azar Dermal Leishmaniasis Caused by Leishmania donovani in Three Patients Co-Infected with Visceral Leishmaniasis and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndro me in Ethiopia.Gelanew T, Hurissa Z, Diro E, Kassahun A, Kuhls K, Schönian G, Hailu A.SourceInstitut für Mikrobiologie und Hygiene, Charité Universitätsmedizin Berlin, Germany; Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia; College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium. AbstractAbstract. We report paired strains of Leishmania parasites, one from the viscera and the other from skin lesions that were isolated from three patients with visceral leishmaniasis and disseminated cutaneous leishmaniasis that were co-infected with human immunodeficiency virus. The causative parasites were characterized by polymerase chain reaction-restriction length polymorphism of the ribosomal DNA internal transcribed spacer 1 and by a panel of multilocus microsatellite markers. We demonstrated that the causative agent was Leishmania donovani in all cases, irrespective of the phenotype of the disease. The paired strains from viscera and skin lesions of the same patients showed genetic identity across the 14 microsatellite markers investigated. These findings demonstrate that the skin lesions in these human immunodeficiency virus-positive patients with visceral leishmaniasis were caused by dissemination of viscerotropic L. donovani parasites as a consequence of severe immunosuppression. However, in all three patients, rapid clearance of the skin lesions was observed after antimonial therapy. |
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| 4. | Am J Trop Med Hyg. 2011 Jun;84(6):901-5.Endemic Tegumentary Leishmaniasis in Brazil: Correlation between Level of Endemicity and Number of Cases of Mucosal Disease.Bedoya-Pacheco SJ, Araujo-Melo MH, Valete-Rosalino CM, Pimentel MI, Conceição-Silva F, Schubach AO, Marzochi MC.SourceEvandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; AbstractAbstract. The purpose of this study was to establish a correlation between the endemic level of tegumentary leishmaniasis in different regions of Brazil during 2002-2009 and the number of cases of mucosal or mucocutaneous leishmaniasis. The proportion of mucosal leishmaniasis was inversely correlated with prevalence of infection. In areas with a lower infection prevalence, the proportion of mucosal leishmaniasis increased (P < 0.05). The hypothesis of an Amazonian origin and dissemination through human migration is considered. Our results show that in regions with lower prevalence and endemically younger, the proportion of cases that evolve to the mucosal form is higher than in regions with higher prevalence and endemically older. |
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| 5. | Am J Trop Med Hyg. 2011 Jun;84(6):892-900.Pharmacokinetics of Oral Sitamaquine Taken with or without Food and Safety and Efficacy for Treatment of Visceral Leishmaniais: A Randomized Study in Bih ar, India.Sundar S, Sinha PK, Dixon SA, Buckley R, Miller AK, Mohamed K, Al-Banna M.SourceKala-azar Medical Research Centre, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India; Rajendra Memorial Research Institute of Medical Sciences, Agamkuan Patna Bihar, India; GlaxoSmithKline, Stockley Park West, United Kingdom; Al-Banna Consulting, LLC, GlaxoSmithKline, King of Prussia, Pennsylvania. AbstractAbstract. This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1-10 and 11-21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)((0-τ)) = 6,627-8,903 ng.hr/mL, AUC((0-16)) = 4,859-6,633 ng.hr/mL, maximum plasma concentration (C(max)) = 401-570 ng/mL, apparent terminal half-life (t(1/2)) = 18.3-22.8 hr, time to reach C(max) (t(max)) = 3.5-6 hr; and desethyl-sitamaquine, AUC((0-τ)) = 2,307-3,163 ng.hr/mL, C(max) = 109-154 ng/mL, t(1/2) = 23.0-27.9 hr, t(max) = 2-10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8-94.4%) for sitamaquine and 95% (95% confidence interval = 75.1-99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis. |
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| 6. | Am J Trop Med Hyg. 2011 Jun;84(6):847-50.A cluster of cutaneous leishmaniasis associated with human smuggling.Cannella AP, Nguyen BM, Piggott CD, Lee RA, Vinetz JM, Mehta SR.SourceDivision of Infectious Diseases and Division of Dermatology, Department of Medicine, University of California San Diego, La Jolla, California. AbstractAbstract. Cutaneous leishmaniasis (CL) is rarely seen in the United States, and the social and geographic context of the infection can be a key to its diagnosis and management. Four Somali and one Ethiopian, in U.S. Border Patrol custody, came to the United States by the same human trafficking route: Djibouti to Dubai to Moscow to Havana to Quito; and then by ground by Columbia/Panama to the United States - Mexico border where they were detained. Although traveling at different times, all five patients simultaneously presented to our institution with chronic ulcerative skin lesions at different sites and stages of evolution. Culture of biopsy specimens grew Leishmania panamensis. Soon thereafter, three individuals from East Africa traveling the identical route presented with L. panamensis CL to physicians in Tacoma, WA. We document here the association of a human trafficking route and new world CL. Clinicians and public health officials should be aware of this emerging infectious disease risk. |
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| 7. | Clin Vaccine Immunol. 2011 Jun 1. [Epub ahead of print]KSAC: the first defined polyprotein vaccine candidate for visceral leishmaniasis.Goto Y, Bhatia A, Raman VS, Liang H, Mohamath R, Picone AF, Vidal SE, Vedvick TS, Howard RF, Reed SG.SourceInfectious Disease Research Institute, Seattle, WA, USA. AbstractA subunit vaccine using defined antigen(s) may be one of the effective solutions to control leishmaniasis. Because of genetic diversity in target populations, including both dogs and humans, a multiple antigen vaccine will likely be essential. However, cost considerations for a vaccine to be used in developing countries must be considered. We report herein a multi-antigen vaccine candidate comprised of antigens known to be protective in animal models, including dogs, as well as to be recognized by humans immune to visceral leishmaniasis. The polyprotein (KSAC) formulated with monophosphoryl lipid A, a widely used adjuvant in human vaccines, was found to be immunogenic and capable of inducing protection against Leishmania infantum responsible for human and canine visceral leishmaniasis as well as against L. major responsible for cutaneous leishmaniasis. The results demonstrate the feasibility of producing a practical, cost effective leishmaniasis vaccine capable of protecting both humans and dogs against multiple Leishmania species. |
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| 8. | J Biol Chem. 2011 May 31. [Epub ahead of print]Substrate preferences and catalytic parameters determined by structural characteristics of Sterol 14{alpha}-demethylase (CYP51) from Leishmania i nfantum.Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI.SourceVanderbilt University, School of Medicine, United States; AbstractLeishmaniasis is a major health problem that affects populations of 88 countries worldwide, with no vaccine and only a few moderately effective drugs. Here we report structure/function characterization of sterol 14α-demethylase (CYP51) from Leishmania infantum. The enzyme catalyzes removal of the 14α-methyl group from sterol precursors. The reaction is essential for membrane biogenesis and therefore has great potential to become a target for antileishmanial chemotherapy. Although L. infantum CYP51 prefers C4-monomethylated sterol substrates, C4-norlanosterol and obtusifoliol (Vmax of 10 and 8 min-1, respectively), it is also found to 14α-demethylate C4-dimethylated lanosterol (Vmax=0.9 min-1) and C4-desmethylated 14α-methylzymosterol (Vmax =1.9 min-1). Binding parameters with six sterols were tested, the Kds ranging within 0.25-1.4 μM. Thus, L. infantum CYP51 is the first example of a plant-like sterol 14α-demethylase, where requirements toward the composition of the C4 atom substituents are not strict, indicative of possible branching in the postsqualene portion of sterol biosynthesis in the parasite. Comparative analysis of three CYP51 substrate binding cavities (Trypanosoma (T) brucei, T. cruzi and L. infantum) suggests that substrate preferences of plant- and fungal-like protozoan CYP51s largely depend on the differences in the enzyme active site topology. These minor structural differences are also likely to underlie CYP51 catalytic rates, drug susceptibility and can be used to design potent and specific inhibitors. |
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| 9. | Mol Microbiol. 2011 Jun 2. doi: 10.1111/j.1365-2958.2011.07721.x. [Epub ahead of print]Lipoamide dehydrogenase is essential for both bloodstream and procyclic Trypanosoma brucei.Roldán A, Comini MA, Crispo M, Krauth-Siegel RL.SourceBiochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany Group Redox Biology of Trypanosomes and Transgenic and Experimental Animal Unit, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400, Montevideo, Uruguay. AbstractLipoamide dehydrogenase (LipDH) is a component of four mitochondrial multienzyme complexes. RNA-interference or the deletion of both alleles in bloodstream Trypanosoma brucei resulted in an absolute requirement for exogenous thymidine. In the absence of thymidine, lipdh-/- parasites showed a severely altered morphology and cell cycle distribution. Most probably, in bloodstream cells with their only rudimentary mitochondrion, LipDH is required as component of the glycine cleavage complex which generates methylene-tetrahydrofolate for dTMP and thus DNA synthesis. The essential role of LipDH in bloodstream parasites was confirmed by an in vivo model. Lipdh-/- cells were unable to infect mice. Our data further revealed that degradation of branched-chain amino acids takes place but is dispensable. In cultured bloodstream - but not procyclic - African trypanosomes, the total cellular concentration of LipDH increases with increasing cell densities. In procyclic parasites, LipDH-mRNA depletion caused an even stronger proliferation defect that was not reversed by thymidine suggesting that in the fully elaborated mitochondrion of these cells the primary effect is not on the glycine cleavage complex. Since the medium used for the cultivation of procyclic cells was not supplemented with glucose, impairment of the 2-ketoglutarate dehydrogenase complex is probably the main effect of LipDH-depletion. © 2011 Blackwell Publishing Ltd. |
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| 10. | Fundam Clin Pharmacol. 2011 Jun 1. doi: 10.1111/j.1472-8206.2011.00955.x. [Epub ahead of print]Physicochemical and biological aspects of macrophage-mediated drug ta rgeting in anti-microbial therapy.Kunjachan S, Jose S, Thomas CA, Joseph E, Kiessling F, Lammers T.SourceDepartment of Pharmaceutical Sciences, Mahatma Gandhi University, Cheruvandoor campus, Ettumanoor 686631, Kerala, India Department of Experimental Molecular Imaging (ExMI), Medical Faculty, University Hospital RWTH- Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany Formulation Development and Pharmacokinetics Lab, Pharmacy Group, FD II, Birla Institute of Technology and Science (BITS), Pilani 333031, Rajasthan, India Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. AbstractMacrophages are important drug targets as they mediate a wide variety of infectious diseases. Visceral leishmaniasis (VL), schistosomiasis, brucellosis, and salmonellosis are some of the well-known infectious diseases in which macrophages play a prominent pathophysiological role. For instance, VL parasites exclusively house in the macrophages of liver and spleen. They are resistant to lysosomal degradation by unknown mechanisms, they survive and thrive safely within macrophages, they multiply, and they ultimately affect visceral organs, leading to severe pathological and sometimes even fatal conditions. The majority of routinely used drugs administered in free form distribute all over the body via systemic circulation, leading to relatively low therapeutic activity and a certain degree of toxicity. Unlike for nonmicrobial diseases, targeting parasites procuring resistance and ineffective therapeutic outcome can be obviously speculated in case of infectious disease. The preferential uptake by macrophages, intended to improve the balance between efficacy and toxicity, can be achieved by the use of nanomedicines, i.e. submicron-sized macromolecular or particulate drug delivery systems. This insight has stimulated researchers to use nanomedicines - which tend to be recognized by macrophages as 'foreign' and consequently are taken up by the intended target cells much more effectively than their free drug counterparts - to improve the treatment of infectious diseases. The literature reports extensively on such approaches; however, there are several constraints that limit the application of nanomedicine in macrophage-mediated drug targeting. Here, we briefly describe the strategies that are used to achieve effective drug targeting to macrophages, using VL as a model disease, and we also put forth an understanding of the most important limiting factors. Various physicochemical and biological factors used by researchers as reported in the literature are addressed, and the most important mechanisms and modes by which macrophage-specific drug targeting can be achieved are summarized. Based on the evidence obtained to date, it can be concluded that targeting macrophages is a valuable and validated strategy for improving the treatment of infectious diseases. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique. |
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