Friday, March 20, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -10 of 14

1: Int J Health Geogr. 2009 Mar 18;8(1):15. [Epub ahead of print]Click here to read

Towards the Atlas of human African trypanosomiasis.

Cecchi G, Paone M, Franco JR, Fevre EM, Diarra A, Ruiz JA, Mattioli RC, Simarro PP.

ABSTRACT: BACKGROUND: Updated, accurate and comprehensive information on the distribution of human African trypanosomiasis (HAT), also known as sleeping sickness, is critically important to plan and monitor control activities. We describe input data, methodology, preliminary results and future prospects of the HAT Atlas initiative, which will allow major improvements in the understanding of the spatial distribution of the disease. METHODS: Up-to-date as well as historical data collected by national sleeping sickness control programmes, non-governmental organizations and research institutes have been collated over many years by the HAT Control and Surveillance Programme of the World Health Organization. This body of information, unpublished for the most part, is now being screened, harmonized, and analysed by means of database management systems and geographical information systems (GIS). The number of new HAT cases and the number of people screened within a defined geographical entity were chosen as the key variables to map disease distribution in sub-Saharan Africa. RESULTS: At the time of writing, over 600 epidemiological reports and files from seventeen countries were collated and included in the data repository. The reports contain information on approximately 20,000 HAT cases, associated to over 7,000 different geographical entities. The oldest epidemiological records considered so far date back to 1985, the most recent having been gathered in 2008. Data from Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea and Gabon from the year 2000 onwards were fully processed and the preliminary regional map of HAT distribution is presented. CONCLUSIONS: The use of GIS tools and geo-referenced, village-level epidemiological data allow the production of maps that substantially improve on the spatial quality of previous cartographic products of similar scope. The significant differences between our preliminary outputs and earlier maps of HAT transmission areas demonstrate the strong need for this systematic approach to mapping sleeping sickness and point to the inaccuracy of any calculation of population at risk based on previous maps of HAT transmission areas. The Atlas of HAT will lay the basis for novel, evidence-based methodologies to estimate the population at risk and the burden of disease, ultimately leading to more efficient targeting of interventions. Also, the Atlas will help streamline future field data collection in those parts of Africa that still require it.

PMID: 19296837 [PubMed - as supplied by publisher]

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2: Biochem J. 2009 Mar 18. [Epub ahead of print]Click here to read

Two pathways for cysteine biosynthesis in Leishmania major.

Williams RA, Westrop GD, Coombs GH.

Genome mining and biochemical analyses have shown that L. major possesses two pathways for cysteine synthesis - the de novo biosynthesis pathway comprising serine acetyltransferase (SAT) and cysteine synthase (CS) and the reverse transsulfuration (RTS) pathway comprising cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL). The L. major CS (LmjCS) is similar to the type A CSs of bacteria and catalyses the synthesis of cysteine using O-acetyserine and sulfide with Kms of 17.5 and 0.13 mM, respectively. LmjCS can use sulfide provided by the action of mercaptopyruvate sulfurtransferase (MST) on 3-mercaptopyruvate (3-MP). LmjCS forms a bi-enzyme complex with Leishmania SAT (and Arabidopsis SAT), with residues K222, H226 and K227 of LmjCS being involved in the complex formation. LmjCBS catalyses the synthesis of cystathionine from homocysteine, but, unlike CBS of mammals, also has high cysteine synthase activity (but with the Km for sulfide being 10.7 mM). In contrast, LmjCS does not have CBS activity. CS was up-regulated when promastigotes are grown in medium with limited availability of sulfur amino acids. Exogenous methionine stimulated growth under these conditions and also the levels of intracellular cysteine, glutathione and trypanothione, whereas cysteine had no effect on growth or the intracellular cysteine levels; correlating with the low rate of transport of cysteine into the cell. These data suggest that cysteine is generated endogenously by promastigotes of Leishmania. The absence of CS from mammals and the clear differences between CBS of mammals and Leishmania suggest that each of the parasite enzymes could be a viable drug target.

PMID: 19296828 [PubMed - as supplied by publisher]

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3: J Med Chem. 2009 Mar 26;52(6):1670-80.Click here to read

Development of a novel virtual screening cascade protocol to identify potential trypanothione reductase inhibitors.

Perez-Pineiro R, Burgos A, Jones DC, Andrew LC, Rodriguez H, Suarez M, Fairlamb AH, Wishart DS.

Department of Biological Sciences and Computing Science, University of Alberta, Edmonton, Alberta, Canada. perezpin@ualberta.ca

The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand-protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadeca-hexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization.

PMID: 19296695 [PubMed - in process]

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4: An Med Interna. 2008 Jun;25(6):279-83.Click here to read

[Visceral leishmaniasis and bronchial asthma: influence of steroid therapy in the development of the macrophage activation syndrome and relative adrenal insufficiency.]

[Article in Spanish]

Ruiz Ginés MA, Ruiz Ginés JA, Menéndez Gómez JL, Pérez Cogolludo AM, Domínguez Martín S, Fernández Rodríguez E.

Servicio de Análisis Clínicos y Bioquímica, Hospital Virgen de la Salud, Illescas, España.

The risk of suffering opportunistics infections in the immunoincompetent patient is a fact perfectly established. An uncommon situation constitutes the bronchopaties, pathologies with a high prevalence among the general population that they require habitually, among other, steroid treatment. The immunosupression confers to the clinical evolution of the infections, as a consequence of the inadequate response to the physical stress, due to the inhibition of the hypothalamus-hypophysis axis being able to in particularly serious cases, to develop the denominated macrophage activation syndrome, a serious and uncommon syndrome that darkens the clinical prognosis in these patients. In presence of a feverish syndrome of uncertain origin in a patient in immunosuppressor treatment, although it is to low dose, it is necessary to carry out a exhaustive differential diagnosis, should consider, among them, the infection for Leishmania, a parasitosis whose incidence is increasing notably in the last years in the immunosuppressed population. We present the clinical case of a 63 year-old patient, immunoincompetent as a consequence of secondary chronic steroid therapy to asthmatic bronchopaty that experiences an uncommon form of visceral leishmaniasis in our area, consistent in multiorganic failure in the context of the development of a macrophage activation syndrome.

PMID: 19295975 [PubMed - in process]

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5: Parasitol Res. 2009 Mar 18. [Epub ahead of print]Click here to read LinkOut

Fast high yield of pure Leishmania (Leishmania) infantum axenic amastigotes and their infectivity to mouse macrophages.

Dias Costa J, Soares R, Cysne Finkelstein L, Côrte-Real S, de Nazareth Meirelles M, Porrozzi R.

Laboratório de Pesquisas em Leishmaniose, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil 4365, Rio de Janeiro, RJ, 21045-900, Brazil.

Leishmania (L.) infantum (syn. Leishmania chagasi) is a dimorphic protozoan parasite that lives in promastigote and amastigote form in its sandfly vector and mammalian hosts, respectively. Here, we describe an in vitro culture system for the generation of a pure population of L. infantum axenic amastigotes after only 4 days incubation in culture medium supplemented with fetal calf serum, human urine, L: -glutamine, and HEPES at 37 masculineC (pH 5.5). Ultrastrutural analysis and infection assays in two macrophage populations (Kupffer cells (KUP) and peritoneal macrophages (PM)) infected with axenic amastigotes demonstrated that they maintained morphological and biochemical (A2 expression) features and a similar infection pattern to tissue-derived L. infantum amastigotes. The susceptibility of the macrophage lines to axenic or tissue-derived amastigotes and promastigotes was investigated. We found a completely different susceptibility profile for KUP and PM. Liver macrophages, both KUP and immigrant macrophages, are intimately involved in the response to L. infantum infection; this difference in susceptibility is probably related to their capacity to eliminate these parasites. Our in vitro system was thus able to generate axenic amastigotes that resemble tissue-derived amastigotes both in morphology and infectivity pattern; this will help in further investigation of the biological characteristics of the host-parasite relationship as well as the process of pathogenesis.

PMID: 19294422 [PubMed - as supplied by publisher]

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6: Arch Dermatol Res. 2009 Mar 18. [Epub ahead of print]Click here to read LinkOut

Isolation of Leishmania amastigote protein fractions which induced lymphocyte stimulation and remission of psoriasis.

O'Daly JA, Lezama R, Gleason J.

Astralis LTD, 75 Passaic Ave., Fairfield, NJ, 07004, USA, joseodaly@aol.com.

A first generation polyvalent vaccine (AS100(1)) was manufactured with protein from several cultured leishmania species, which proved to be effective in the treatment of psoriasis. To determine the effective factor, a single blind trial with four monovalent second generation vaccines (AS100(2)) was done in 26 subjects, which also resulted in remission of psoriasis. AS100(2) vaccines were further purified, resulting in seven chromatography fractions (AS200) per species. In vitro testing of the fractions on blood lymphocytes resulted in subjects being categorized as low or high responders before treatment. Both responder groups had no statistical difference in clinical outcome after AS100(1) treatment. Subsequently, a single-blind trial in 55 subjects treated with AS200 fractions from Leishmania brasiliensis also induced remission of Psoriasis. Two HIV +/- subjects with plaque psoriasis experienced remission after treatment with AS100(1). There are factors in leishmania species which induce remission of psoriasis by stimulating lymphocytes.

PMID: 19294395 [PubMed - as supplied by publisher]

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7: Plant Cell. 2009 Mar 17. [Epub ahead of print]Click here to read LinkOut

Uridine-Ribohydrolase Is a Key Regulator in the Uridine Degradation Pathway of Arabidopsis.

Jung B, Flörchinger M, Kunz HH, Traub M, Wartenberg R, Jeblick W, Neuhaus HE, Möhlmann T.

Abteilung Pflanzenphysiologie, Fachbereich Biologie, Technische Universität Kaiserslautern, D-67663 Kaiserslautern, Germany.

Nucleoside degradation and salvage are important metabolic pathways but hardly understood in plants. Recent work on human pathogenic protozoans like Leishmania and Trypanosoma substantiates an essential function of nucleosidase activity. Plant nucleosidases are related to those from protozoans and connect the pathways of nucleoside degradation and salvage. Here, we describe the cloning of such an enzyme from Arabidopsis thaliana, Uridine-Ribohydrolase 1 (URH1) and the characterization by complementation of a yeast mutant. Furthermore, URH1 was synthesized as a recombinant protein in Escherichia coli. The pure recombinant protein exhibited highest hydrolase activity for uridine, followed by inosine and adenosine, the corresponding K m values were 0.8, 1.4, and 0.7 mM, respectively. In addition, URH1 was able to cleave the cytokinin derivative isopentenyladenine-riboside. Promoter beta-glucuronidase fusion studies revealed that URH1 is mainly transcribed in the vascular cells of roots and in root tips, guard cells, and pollen. Mutants expressing the Arabidopsis enzyme or the homolog from rice (Oryza sativa) exhibit resistance toward toxic fluorouridine, fluorouracil, and fluoroorotic acid, providing clear evidence for a pivotal function of URH1 as regulative in pyrimidine degradation. Moreover, mutants with increased and decreased nucleosidase activity are delayed in germination, indicating that this enzyme activity must be well balanced in the early phase of plant development.

PMID: 19293370 [PubMed - as supplied by publisher]

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8: Parasite Immunol. 2009 Apr;31(4):199-209.Click here to read LinkOut

Evaluation of T cell responses in healing and nonhealing leishmaniasis reveals differences in T helper cell polarization ex vivo and in vitro.

Choi BS, Kropf P.

Department of Immunology, Faculty of Medicine, Imperial College London, UK.

Experimental leishmaniasis is widely used to study the effector functions of T helper cell subsets in vivo. Healing and nonhealing Leishmania major infections have been correlated with T helper 1 and T helper 2 responses, respectively. In the present study, we determined T cell effector functions ex vivo, without any further restimulation and compared them to those obtained following antigen-specific restimulation in vitro. Our results show that T helper cell responses are significantly less polarized when determined ex vivo as compared to those measured after restimulation in vitro. Moreover, the differences in CD4(+) T cell proliferation observed between healer and nonhealer strains of mice differed ex vivo and in vitro. Our results suggest that determination of both ex vivo as well as in vitro T cell responses is crucial to characterize immune responses during experimental leishmaniasis.

PMID: 19292771 [PubMed - in process]

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9: Parasite Immunol. 2009 Apr;31(4):188-98.Click here to read LinkOut

The scavenger receptor MARCO is involved in Leishmania major infection by CBA/J macrophages.

Gomes IN, Palma LC, Campos GO, Lima JG, DE Almeida TF, DE Menezes JP, Ferreira CA, Santos RR, Buck GA, Manque PA, Ozaki LS, Probst CM, DE Freitas LA, Krieger MA, Veras PS.

Centro de Pesquisas Gonçalo Moniz, FIOCRUZ-BA, Brazil.

CBA/J mice are resistant to Leishmania major infection but are permissive to L. amazonensis infection. In addition, CBA/J macrophages control L. major but not L. amazonensis infection in vitro. Phagocytosis by macrophages is known to determine the outcome of Leishmania infection. Pattern recognition receptors (PRR) adorning antigen presenting cell surfaces are known to coordinate the link between innate and adaptive immunity. The macrophage receptor with collagenous structure (MARCO) is a PRR that is preferably expressed by macrophages and is capable of binding Gram-positive and Gram-negative bacteria. No research on the role of MARCO in Leishmania-macrophage interactions has been reported. Here, we demonstrate, for the first time, that MARCO expression by CBA/J macrophages is increased in response to both in vitro and in vivo L. major infections, but not to L. amazonensis infection. In addition, a specific anti-MARCO monoclonal antibody reduced L. major infection of macrophages by 30%-40% in vitro. The draining lymph nodes of anti-MARCO-treated mice displayed a reduced presence of immunolabelled parasite and parasite antigens, as well as a reduced inflammatory response. These results support the hypothesis that MARCO has a role in macrophage infection by L. major in vitro as well as in vivo.

PMID: 19292770 [PubMed - in process]

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10: Curr Protoc Protein Sci. 2009 Feb;Chapter 19:Unit 19.19.Click here to read LinkOut

Tandem affinity purification of proteins.

Günzl A, Schimanski B.

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.

Tandem affinity purification (TAP) is a very efficient method to isolate proteins, protein complexes, or ribonucleoprotein particles from crude extracts. The method depends on the expression of one protein component fused N- or C-terminally to a TAP tag in the organism of interest. The TAP tag is a composite tag consisting of two different epitope domains and a protease cleavage site, and it facilitates the purification of the tagged protein in two consecutive, high-affinity chromatography steps. Combined, the two steps are typically so efficient that a protein complex can be purified virtually to homogeneity without the need for protein overexpression. If the tag does not interfere with protein function, TAP is likely to yield an intact protein complex because all steps of the procedure are carried out under nondenaturing conditions. In this unit, a TAP procedure is detailed which employs a novel epitope combination termed PTP.

PMID: 19235137 [PubMed - indexed for MEDLINE]

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