Wednesday, October 7, 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 -8 of 8

1: J Clin Oncol. 2009 Oct 5. [Epub ahead of print]

Coexistence of Leishmaniasis and Hodgkin's Lymphoma in a Lymph Node.

Domingues M, Menezes Y, Ostronoff F, Calixto R, Florencio R, Sucupira A, Souto-Maior AP, Ostronoff M.

Hematology and Bone Marrow Transplantation Unit, Real-Hospital Português, Recife, Brazil.

PMID: 19805673 [PubMed - as supplied by publisher]

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2: Antimicrob Agents Chemother. 2009 Oct 5. [Epub ahead of print]

Amiodarone and miltefosine act synergistically against Leishmania mexicana and can induce parasitological cure in a murine model of cutaneous leishmaniasis.

Serrano-Martín X, Payares G, De Lucca M, Martinez JC, Mendoza-León A, Benaim G.

Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela; and Instituto de Biología Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela.

Leishmaniasis is parasitic disease that is an important problem of public health worldwide. Intramuscular-administered glucantime and pentostam are the most common drugs used for treatment of this disease, but they have significant limitations due to toxicity and increasing resistance. A recent breakthrough has been the introduction of orally administered miltefosine for the treatment of visceral, cutaneous and muco-cutaneous leishmaniasis, but the relative high cost and concerns about teratogenicity have limited the use of this drug. Searching for alternative drugs, we have previously demonstrated that the antiarrhythmic drug amiodarone is active against Leishmania mexicana promastigotes and intracellular amastigotes, acting via disruption of the intracellular Ca(2+) homeostasis (specifically at the mitochondrion and the acidocalcisomes of these parasites) and through inhibition of the parasite's de novo sterol biosynthesis (Serrano-Martín, X., García-Marchan, Y., Fernandez, A., Rodriguez, N., Rojas, H., Visbal, G. and Benaim, G. 2009. Antimicrob. Agents Chemother. 53:1403-1410). In the present work we found that miltefosine also disrupts the parasite intracellular Ca(2+) homeostasis, in this case by inducing a large increase in intracellular Ca(2+) levels, probably through the activation of a plasma membrane Ca(2+) channel. We also investigated the in vitro and in vivo activities of amiodarone and miltefosine, used alone or in combination, on L. mexicana. It was found that the drug combination had synergistic effects on the proliferation of intracellular amastigotes growing inside macrophages and led 90% of parasitological cures in a murine model of leishmaniasis, as revealed by a PCR assay using a novel DNA sequence specific for Leishmania mexicana.

PMID: 19805563 [PubMed - as supplied by publisher]

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3: Mol Cell Biol. 2009 Oct 5. [Epub ahead of print]

Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and Type I interferon signaling.

Liu J, Carvalho LP, Bhattachariya S, Carbone CJ, Kumar KG, Leu NA, Yau PM, Donald RG, Weiss MJ, Baker DP, McLaughlin KJ, Scott P, Fuchs SY.

Department of Animal Biology and Mari Lowe Center for Comparative Oncology, and Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065; Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Biogen Idec Inc., Cambridge, MA 02142, USA.

Phosphorylation of the degron of the IFNAR1 chain of Type I IFN receptor triggers ubiquitination and degradation of this receptor, and, therefore, plays a crucial role in negative regulation of IFNalpha/beta signaling. Besides IFN-stimulated and Jak activity-dependent pathway, a basal ligand-independent phosphorylation of IFNAR1 has been described and implicated in downregulating IFNAR1 in response to virus-induced ER stress. Here we report purification and characterization of CK1alpha as a bona fide major IFNAR1 kinase that confers basal turnover of IFNAR1 and cooperates with ER stress stimuli to mediate phosphorylation-dependent degradation of IFNAR1. Activity of CK1alpha was required for phosphorylation and downregulation of IFNAR1 in response to ER stress and viral infection. While many forms of CK1 were capable of phosphorylating IFNAR1 in vitro, human CK1alpha and L-CK1 produced by the protozoan Leishmania major were also capable of increasing the IFNAR1 degron phosphorylation in cells. Expression of L-CK1 in mammalian cells stimulated the phosphorylation-dependent downregulation of IFNAR1 and attenuated its signaling. Infection of mammalian cells with L. major modestly decreased IFNAR1 levels and attenuated cellular responses to IFNalpha in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and Type I IFN signaling.

PMID: 19805514 [PubMed - as supplied by publisher]

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4: Proc Natl Acad Sci U S A. 2009 Sep 9. [Epub ahead of print]

A human IL10 BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcome.

Ranatunga D, Hedrich CM, Wang F, McVicar DW, Nowak N, Joshi T, Feigenbaum L, Grant LR, Stäger S, Bream JH.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205-1901.

Interleukin (IL)-10 is an immunoregulatory cytokine that is produced by diverse cell populations. Studies in mice suggest that the cellular source of IL-10 is a key determinant in various disease pathologies, yet little is known regarding the control of tissue-specific human IL-10 expression. To assess cell type-specific human IL-10 regulation, we created a human IL-10 transgenic mouse with a bacterial artificial chromosome (hIL10BAC) in which the IL10 gene is positioned centrally. Since human IL-10 is biologically active in the mouse, we could examine the in vivo capacity of tissue-specific human IL-10 expression to recapitulate IL-10-dependent phenotypes by reconstituting Il10(-/-) mice (Il10(-/-)/hIL10BAC). In response to LPS, Il10(-/-)/hIL10BAC mice proficiently regulate IL-10-target genes and normalize sensitivity to LPS toxicity via faithful human IL-10 expression from macrophages and dendritic cells. However, in the Leishmania donovani model of pathogen persistence, Il10(-/-)/hIL10BAC mice did not develop the characteristic IL-10(+)IFN-gamma(+)CD4 T cell subset thought to mediate persistence and, like Il10(-/-) mice, cleared the parasites. Furthermore, the IL-10-promoting cytokine IL-27 failed to regulate transgenic human IL-10 production in CD4(+) T cells in vitro which together suggests that the hIL10BAC encodes for weak T cell-specific IL-10 expression. Thus, the hIL10BAC mouse is a model of human gene structure and function revealing tissue-specific regulatory requirements for IL-10 expression which impacts disease outcomes.

PMID: 19805095 [PubMed - as supplied by publisher]

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5: Infect Genet Evol. 2009 Mar 3. [Epub ahead of print]

Vaccine development against Trypanosoma cruzi and Leishmania species in the post-genomic era.

Dumonteil E.

Laboratorio de Parasitología, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Merida, Yucatan, Mexico; Department of Tropical Medicine, Tulane University, School of Public Health and Tropical Medicine, New Orleans, LO, USA.

Trypanosoma cruzi and the genus Leishmania are protozoan parasites causing diseases of major public health importance, and the recent completion of the sequencing of their genomes has opened new opportunities to further our understanding of the mechanisms required for protection and the development of vaccines. For example, trans-sialidases, one of the largest protein families from T. cruzi, contain dominant CD8(+) T cell epitopes, and their use as preventive or therapeutic vaccines in different animal models has provided encouraging results. A much wider range of antigens and vaccine formulations have been tested against Leishmania, and new correlates for protection are being defined, such as the induction of multifunctional Th1 effector cells capable of producing a complex set of cytokines. Also, while a large number of these vaccine candidates have been rather successful in mouse models, their usefulness in more relevant animal models is still poor, in spite of significant immunogenicity. Novel proteomics and genomics approaches are being used for antigen discovery and the identification of new vaccine candidates, some of which have shown promise for the control of infection. These studies cast little doubt that T. cruzi and Leishmania genomes represent major resources for understanding key aspects of the mechanisms of immune protection against these parasites, and the increasing use of these tools will greatly impact vaccine development.

PMID: 19805015 [PubMed - as supplied by publisher]

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6: BMC Med. 2009 Oct 5;7(1):54. [Epub ahead of print]

Chemical and environmental vector control as a contribution to the elimination of visceral leishmaniasis on the Indian subcontinent: cluster randomized controlled trials in Bangladesh, India and Nepal.

Joshi AB, Das ML, Akhter S, Chowdhury R, Mondal D, Kumar V, Das P, Kroeger A, Boelaert M, Petzold M.

ABSTRACT: BACKGROUND: Bangladesh, India and Nepal are working towards the elimination of visceral leishmaniasis (VL) by 2015. In 2005 the World Health Organization/Training in Tropical Diseases launched an implementation research programme to support integrated vector management for the elimination of VL from Bangladesh, India and Nepal. The programme is conducted in different phases, from proof-of-concept to scaling up intervention. This study was designed in order to evaluate the efficacy of the three different interventions for VL vector management: indoor residual spraying (IRS); long-lasting insecticide treated nets (LLIN); and environmental modification (EVM) through plastering of walls with lime or mud. METHODS: Using a cluster randomized controlled trial we compared three vector control interventions with a control arm in 96 clusters (hamlets or neighbourhoods) in each of the 4 study sites: Bangladesh (one), India (one) and Nepal (two). In each site four villages with high reported VL incidences were included. In each village six clusters and in each cluster five households were randomly selected for sand fly collection on two consecutive nights. Control and intervention clusters were matched with average pre-intervention vector densities. In each site six clusters were randomly assigned to each of the following interventions: indoor residual spraying (IRS); long-lasting insecticide treated nets (LLIN); environmental management (EVM) or control. All the houses (50-100) in each intervention cluster underwent the intervention measures. A reduction of intra-domestic sand fly densities measured by overnight US Centres for Disease Prevention and Control light trap captures (that is the number of sand flies per trap per night) was the main outcome measure. RESULTS: IRS, and to a lesser extent EVM and LLINs, significantly reduced sand fly densities for at least 5 months in the study households irrespective of type of walls or whether or not people shared their house with cattle. IRS was effective in all sites but LLINs were only effective in Bangladesh and India. Mud plastering did not reduce sand fly density (Bangladesh study); lime plastering in India and one Nepali site, resulted in a significant reduction of sand fly density but not in the second Nepali site. CONCLUSIONS: Sand fly control can contribute to the regional VL elimination programme; IRS should be strengthened in India and Nepal but in Bangladesh, where vector control has largely been abandoned during the last decades, the insecticide treatment of existing bed nets (coverage above 90% in VL endemic districts) could bring about an immediate reduction of vector populations; operational research to inform policy makers about the efficacious options for VL vector control and programme performance should be strengthened in the three countries.

PMID: 19804620 [PubMed - as supplied by publisher]

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7: J Parasitol. 2009 Oct 5:1. [Epub ahead of print]

SURVEILLANCE FOR ANTIBODIES TO LEISHMANIA SPP. IN DOGS FROM SRI LANKA.

Rosypal AC, Tripp S, Kinlaw C, Hailemariam S, Tidwell RR, Lindsay DS, Rajapakse RP, Sreekumar C, Dubey JP.

The global distribution of leishmaniasis is rapidly expanding into new geographic regions. Dogs are the primary reservoir hosts for human visceral leishmaniasis caused by infection with Leishmania infantum. Natural infections with other Leishmania species can occur in dogs, but their role as reservoir hosts for other species of Leishmania is uncertain. Leishmania donovani is traditionally considered a visceralizing anthroponotic species, however, cutaneous leishmaniasis caused by L. donovani has been reported in Sri Lanka. In the present study, serum from 114 dogs in Sri Lanka were examined for antibodies to visceralizing Leishmania parasites. Sera were tested by the canine immunochromatographic strip assays based on recombinant K39 antigen. Anti-Leishmania antibodies were detectable in 1 of 114 (0.9%) dogs from Sri Lanka. Serological evidence suggests that leishmaniasis may be an emerging zoonosis in Sri Lanka.

PMID: 19803542 [PubMed - as supplied by publisher]

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8: Medicina (B Aires). 2008;68(5):398-404.LinkOut

[Trypanosoma cruzi: transport of essential metabolites acquired from the host]

[Article in Spanish]

Pereira CA, Carrillo C, Miranda MR, Bouvier LA, Cánepa GE.

Laboratorio de Biología Molecular de Trypanosoma cruzi, Instituto de Investigaciones Médicas Alfredo P. Lanari, (UBA-CONICET) Facultad de Medicina. cpereira@mail.retina.ar

Trypanosoma cruzi is the etiological agent of Chagas disease, a disease endemic not only in Argentina but also in all of Latin America. T. cruzi presents several metabolic characteristics which are completely absent in its insect vectors and in mammalian hosts. Some of these differences were acquired after millions of years of adaptation to parasitism, during which this protozoan replaced many biosynthetic routes for transport systems. In the present review, we describe the advances in the knowledge of T. cruzi transport processes and the molecules involved. In particular, we focus on amino acid and polyamine transporters from the AAAP family (Amino Acid/Auxin Permeases), because they seem to be exclusive transporters from trypanosomatids. Taking into account that these permeases are completely absent in mammals, they could be considered as a potential target against Trypanosoma cruzi.

PMID: 18977714 [PubMed - indexed for MEDLINE]

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