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 21

1.	Cytometry A. 2010 Dec 13. [Epub ahead of print] Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis. Sarkar A, Saha P, Mandal G, Mukhopadhyay D, Roy S, Singh SK, Das S, Goswami RP, Saha B, Kumar D, Das P, Chatterjee M. Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata 700 020, India. Abstract Nitric oxide (NO) has been demonstrated to be a principal effector molecule responsible for mediating intracellular killing of Leishmania parasites, the causative organism of leishmaniasis. As measurement of intracellular NO remains a challenge to biologists, we have developed a flow cytometric approach to perform real time biological detection of NO within Leishmania parasites and parasitized macrophages using a membrane permeable derivative of diaminofluorescein [4,5-diaminofluorescein diacetate (DAF-2DA)]. Initially, assay optimization was performed in Leishmania donovani promastigotes, assay specificity being confirmed using both a NO donor [S-nitroso-N-acetyl-penicillamine (SNAP)] and a NO scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, C-PTIO]. Using 40 μM DAF-2DA, basal levels of intracellular NO were measured which varied in different Leishmania species; addition of conventional anti-leishmanial drugs, antimony and miltefosine translated into a dramatic increase in DAF-2T fluorescence. Furthermore, the assay also measured levels of NO in macrophages, but needed a 20 fold lower concentration of DAF-2DA, being 2 μM. Following parasitization, levels of NO decreased which was normalized following treatment with anti-leishmanial drugs. Similarly monocytes of patients with visceral leishmaniasis at disease presentation showed decreased levels of NO which too reverted on completion of treatment. Taken together, this study opens new perspectives of research regarding monocyte function and provides a real time approach for monitoring the effect of anti-leishmanial compounds. © 2010 International Society for Advancement of Cytometry.
	PMID: 21154977 [PubMed - as supplied by publisher]

2.	Braz J Med Biol Res. 2010 Dec 10. pii: S0100-879X2010007500141. [Epub ahead of print] Photodynamic antimicrobial chemotherapy (PACT) for the treatment of malaria, leishmaniasis and trypanosomiasis. Baptista MS, Wainwright M. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
	PMID: 21152709 [PubMed - as supplied by publisher]

3.	Rev Saude Publica. 2010 Dec 10. pii: S0034-89102010005000053. [Epub ahead of print] [Ethics in the publication of studies on human visceral leishmaniasis in Brazilian periodicals.] [Article in Portuguese] Malafaia G, Rodrigues AS, Talvani A. Departamento de Ciências Biológicas, Núcleo de Pesquisa em Ciências Ambientais e Biológicas, Instituto Federal de Educação, Ciência e Tecnologia Goiano, Urutaí, GO, Brasil. Abstract OBJECTIVE: To analyze ethical aspects of Brazilian articles on human visceral leishmaniasis, published after Resolution CNS 196/1996, and to analyze the policy on Brazilian periodicals on research ethics. METHODS: An explanatory study with a bibliographical and documental nature was conducted. Selection of publications on research involving human beings since 1996 was performed in the SciELO Brazil database. Gaps associated with editorial policies on medical periodicals, based on information obtained from the "Instructions to authors" section of each periodical, were analyzed. RESULTS: While there were no articles on the compliance with ethical aspects in the first four-year period (from 1997 to 2000), 75% fulfilled at least one of the ethical requirements evaluated in the first year (2009) of a subsequent four-year period (from 2009 to 2012). A total of six out of 11 periodicals indicated that the information about ethical aspects should be mentioned in the body of the article. There were three periodicals that required a letter or document, informing about compliance with these aspects and signed by the author(s), to be sent; two that requested a copy of the document used to obtain the free and informed consent; one that clarified the need of a copy to authorize the approval by the Committee on Ethics in Research; and four in which no requirements of ethical aspects were found. CONCLUSIONS: There was an improvement in the description of compliance with ethical aspects found in articles. Standardization of ethical requirements for human research in Brazilian periodicals is suggested. This could promote compliance with the presuppositions of documents regulating human research.
	PMID: 21152706 [PubMed - as supplied by publisher]

4.	PLoS Negl Trop Dis. 2010 Nov 30;4(11):e901. Targeting the Midgut Secreted PpChit1 Reduces Leishmania major Deve lopment in Its Natural Vector, the Sand Fly Phlebotomus papatasi. Coutinho-Abreu IV, Sharma NK, Robles-Murguia M, Ramalho-Ortigao M. Department of Entomology, Kansas State University, Manhattan, Kansas, United States of America. Abstract BACKGROUND: During its developmental cycle within the sand fly vector, Leishmania must survive an early proteolytic attack, escape the peritrophic matrix, and then adhere to the midgut epithelia in order to prevent excretion with remnants of the blood meal. These three steps are critical for the establishment of an infection within the vector and are linked to interactions controlling species-specific vector competence. PpChit1 is a midgut-specific chitinase from Phlebotomus papatasi presumably involved in maturation and degradation of the peritrophic matrix. Sand fly midgut chitinases, such as PpChit1, whether acting independently or in a synergistic manner with Leishmania-secreted chitinase, possibly play a role in the Leishmania escape from the endoperitrophic space. Thus, we predicted that silencing of sand fly chitinase will lead to reduction or elimination of Leishmania within the gut of the sand fly vector. METHODOLOGY/PRINCIPAL FINDINGS: We used injection of dsRNA to induce knock down of PpChit1 transcripts (dsPpChit1) and assessed the effect on protein levels post blood meal (PBM) and on Leishmania major development within P. papatasi. Injection of dsPpChit1 led to a significant reduction of PpChit1 transcripts from 24 hours to 96 hours PBM. More importantly, dsPpChit1 led to a significant reduction in protein levels and in the number of Le. major present in the midgut of infected P. papatasi following a infective blood meal. CONCLUSION/SIGNIFICANCE: Our data supports targeting PpChit1 as a potential transmission blocking vaccine candidate against leishmaniasis.
	PMID: 21152058 [PubMed - as supplied by publisher]

5.	PLoS Negl Trop Dis. 2010 Nov 30;4(11):e904. Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations. T'kindt R, Scheltema RA, Jankevics A, Brunker K, Rijal S, Dujardin JC, Breitling R, Watson DG, Coombs GH, Decuypere S. Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium. Abstract Leishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to antimonial treatment due to differing intrinsic drug sensitivity of the parasites. Here, we present a proof-of-principle study in which we applied a metabolomics pipeline specifically developed for L. donovani to characterize the global metabolic differences between antimonial-sensitive and antimonial-resistant L. donovani isolates. Clones of drug-sensitive and drug-resistant parasite isolates from clinical samples were cultured in vitro and harvested for metabolomics analysis. The relative abundance of 340 metabolites was determined by ZIC-HILIC chromatography coupled to LTQ-Orbitrap mass spectrometry. Our measurements cover approximately 20% of the predicted core metabolome of Leishmania and additionally detected a large number of lipids. Drug-sensitive and drug-resistant parasites showed distinct metabolic profiles, and unsupervised clustering and principal component analysis clearly distinguished the two phenotypes. For 100 metabolites, the detected intensity differed more than three-fold between the 2 phenotypes. Many of these were in specific areas of lipid metabolism, suggesting that the membrane composition of the drug-resistant parasites is extensively modified. Untargeted metabolomics has been applied on clinical Leishmania isolates to uncover major metabolic differences between drug-sensitive and drug-resistant isolates. The identified major differences provide novel insights into the mechanisms involved in resistance to antimonial drugs, and facilitate investigations using targeted approaches to unravel the key changes mediating drug resistance.
	PMID: 21152055 [PubMed - as supplied by publisher]

6.	PLoS One. 2010 Dec 6;5(12):e14239. Genetic and Chemical Evaluation of Trypanosoma brucei Oleate Desaturase as a Candidate Drug Target. Alloatti A, Gupta S, Gualdrón-López M, Igoillo-Esteve M, Nguewa PA, Deumer G, Wallemacq P, Altabe SG, Michels PA, Uttaro AD. Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Biología Molecular y Celular de Rosario, CONICET, Universidad Nacional de Rosario, Rosario, Santa Fe, Argentina. Abstract BACKGROUND: Trypanosomes can synthesize polyunsaturated fatty acids. Previously, we have shown that they possess stearoyl-CoA desaturase (SCD) and oleate desaturase (OD) to convert stearate (C18) into oleate (C18:1) and linoleate (C18:2), respectively. Here we examine if OD is essential to these parasites. METHODOLOGY: Cultured procyclic (insect-stage) form (PCF) and bloodstream-form (BSF) Trypanosoma brucei cells were treated with 12- and 13-thiastearic acid (12-TS and 13-TS), inhibitors of OD, and the expression of the enzyme was knocked down by RNA interference. The phenotype of these cells was studied. PRINCIPAL FINDINGS: Growth of PCF T. brucei was totally inhibited by 100 µM of 12-TS and 13-TS, with EC(50) values of 40±2 and 30±2 µM, respectively. The BSF was more sensitive, with EC(50) values of 7±3 and 2±1 µM, respectively. This growth phenotype was due to the inhibitory effect of thiastearates on OD and, to a lesser extent, on SCD. The enzyme inhibition caused a drop in total unsaturated fatty-acid level of the cells, with a slight increase in oleate but a drastic decrease in linoleate level, most probably affecting membrane fluidity. After knocking down OD expression in PCF, the linoleate content was notably reduced, whereas that of oleate drastically increased, maintaining the total unsaturated fatty-acid level unchanged. Interestingly, the growth phenotype of the RNAi-induced cells was similar to that found for thiastearate-treated trypanosomes, with the former cells growing twofold slower than the latter ones, indicating that the linoleate content itself and not only fluidity could be essential for normal membrane functionality. A similar deleterious effect was found after RNAi in BSF, even with a mere 8% reduction of OD activity, indicating that its full activity is essential. CONCLUSIONS/SIGNIFICANCE: As OD is essential for trypanosomes and is not present in mammalian cells, it is a promising target for chemotherapy of African trypanosomiasis.
	PMID: 21151902 [PubMed - as supplied by publisher]

7.	PLoS Negl Trop Dis. 2010 Dec 7;4(12):e913. A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model. Wasan EK, Gershkovich P, Zhao J, Zhu X, Werbovetz K, Tidwell RR, Clement JG, Thornton SJ, Wasan KM. School of Health Sciences, British Columbia Institute of Technology, Burnaby, Canada. Abstract PURPOSE: To develop an oral formulation of amphotericin B (AmB) that is stable at the temperatures of WHO Climatic Zones 3 and 4 (30-43°C) and to evaluate its efficacy in a murine model of visceral leishmaniasis (VL). METHODS: The stability testing of four novel oral lipid AmB formulations composed of mono- and di-glycerides and pegylated esters (iCo-010 to iCo-013) was performed over 60 d and analyzed by HPLC-UV. In addition, the four formulations were incubated 4 h in fasted-state simulated intestinal fluid. AmB concentration was measured spectrophotometrically and emulsion droplet diameter was assessed by dynamic light scattering. Antileishmanial activity of iCo-010 was evaluated at increasing oral doses (2.5 to 10 mg/kg) in a murine model of VL. RESULTS: AmB stability in the lipid formulation (iCo-010) was >75% over 60 days. After 4 h in fasted-state simulated intestinal fluid, AmB concentration was >95%. iCo-010 demonstrated significant efficacy when orally administered to VL-infected mice bid for five days (inhibition of 99%, 98%, and 83% at 10, 5 and 2.5 mg/kg compared to the vehicle control). In addition, the qd dose of 20 mg/kg provided 96% inhibition compared to the vehicle control. CONCLUSIONS: The oral AmB formulation iCo-010 is stable at the temperatures of WHO Climatic Zones 3 and 4 (30-43°C). iCo-010 showed excellent antileishmanial activity at both 10 mg/kg po bid for 5 days (<99% reduction in parasitic infection) and 20 mg/kg po qd for 5 days (95% inhibition when compared to control).
	PMID: 21151883 [PubMed - as supplied by publisher]

8.	PLoS Negl Trop Dis. 2010 Dec 7;4(12):e906. Focus-Specific Clinical Profiles in H uman African Trypanosomiasis Caused by Trypanosoma brucei rhodesiense. Maclean LM, Odiit M, Chisi JE, Kennedy PG, Sternberg JM. Department of Biology, Hull York Medical School, Centre for Immunology and Infection, University of York, York, United Kingdom. Abstract BACKGROUND: Diverse clinical features have been reported in human African trypanosomiasis (HAT) foci caused by Trypanosoma brucei rhodesiense (T.b.rhodesiense) giving rise to the hypothesis that HAT manifests as a chronic disease in South-East African countries and increased in virulence towards the North. Such variation in disease severity suggests there are differences in host susceptibility to trypanosome infection and/or genetic variation in trypanosome virulence. Our molecular tools allow us to study the role of host and parasite genotypes, but obtaining matched extensive clinical data from a large cohort of HAT patients has previously proved problematic. METHODS/PRINCIPAL FINDINGS: We present a retrospective cohort study providing detailed clinical profiles of 275 HAT patients recruited in two northern foci (Uganda) and one southern focus (Malawi) in East Africa. Characteristic clinical signs and symptoms of T.b.rhodesiense infection were recorded and the degree of neurological dysfunction determined on admission. Clinical observations were mapped by patient estimated post-infection time. We have identified common presenting symptoms in T.b.rhodesiense infection; however, marked differences in disease progression and severity were identified between foci. HAT was characterised as a chronic haemo-lymphatic stage infection in Malawi, and as an acute disease with marked neurological impairment in Uganda. Within Uganda, a more rapid progression to meningo-encephaltic stage of infection was observed in one focus (Soroti) where HAT was characterised by early onset neurodysfunction; however, severe neuropathology was more frequently observed in patients in a second focus (Tororo). CONCLUSIONS/SIGNIFICANCE: We have established focus-specific HAT clinical phenotypes showing dramatic variations in disease severity and rate of stage progression both between northern and southern East African foci and between Ugandan foci. Understanding the contribution of host and parasite factors in causing such clinical diversity in T.b.rhodesiense HAT has much relevance for both improvement of disease management and the identification of new drug therapy.
	PMID: 21151878 [PubMed - as supplied by publisher]

9.	PLoS Negl Trop Dis. 2010 Dec 7;4(12):e905. Fusion between Leishmania amazonensis and Leishmania ma jor Parasitophorous Vacuoles: Live Imaging of Coinfected Macrophages. Real F, Mortara RA, Rabinovitch M. Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil. Abstract Protozoan parasites of the genus Leishmania alternate between flagellated, elongated extracellular promastigotes found in insect vectors, and round-shaped amastigotes enclosed in phagolysosome-like Parasitophorous Vacuoles (PVs) of infected mammalian host cells. Leishmania amazonensis amastigotes occupy large PVs which may contain many parasites; in contrast, single amastigotes of Leishmania major lodge in small, tight PVs, which undergo fission as parasites divide. To determine if PVs of these Leishmania species can fuse with each other, mouse macrophages in culture were infected with non-fluorescent L. amazonensis amastigotes and, 48 h later, superinfected with fluorescent L. major amastigotes or promastigotes. Fusion was investigated by time-lapse image acquisition of living cells and inferred from the colocalization of parasites of the two species in the same PVs. Survival, multiplication and differentiation of parasites that did or did not share the same vacuoles were also investigated. Fusion of PVs containing L. amazonensis and L. major amastigotes was not found. However, PVs containing L. major promastigotes did fuse with pre-established L. amazonensis PVs. In these chimeric vacuoles, L. major promastigotes remained motile and multiplied, but did not differentiate into amastigotes. In contrast, in doubly infected cells, within their own, unfused PVs metacyclic-enriched L. major promastigotes, but not log phase promastigotes - which were destroyed - differentiated into proliferating amastigotes. The results indicate that PVs, presumably customized by L. major amastigotes or promastigotes, differ in their ability to fuse with L. amazonensis PVs. Additionally, a species-specific PV was required for L. major destruction or differentiation - a requirement for which mechanisms remain unknown. The observations reported in this paper should be useful in further studies of the interactions between PVs to different species of Leishmania parasites, and of the mechanisms involved in the recognition and fusion of PVs.
	PMID: 21151877 [PubMed - as supplied by publisher]

10.	Infect Immun. 2010 Dec 13. [Epub ahead of print] IRF-7 contributes to the control of Leishmania donovani in the mouse liver. Beattie L, Phillips R, Brown N, Owens BM, Chauhan N, Dalton JE, Kaye PM. Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, Wentworth Way, York YO10 5YW, U.K. Abstract Optimal hepatic resistance to Leishmania donovani in mice requires the coordinated effort of a variety of leucocyte populations that together induce activation of local macrophages to a leishmanicidal state. Although nitric oxide and reactive oxygen intermediates are potent leishmanicidal effector molecules operating in the acquired phase of immunity, there have long been suggestions that other mechanisms of leishmanicidal activity exist. We recently discovered that Irf-7 regulates a novel innate leishmanicidal response in resident splenic macrophages that line the marginal zone. Here, we tested whether this mechanism also operated in Kupffer cells, the resident macrophage population of the liver and the major target for hepatic infection by L. donovani. Comparing the Kupffer cell response in situ in B6 and B6.Irf-7(-/-) mice, we found no evidence that Irf-7 affected amastigote uptake or early survival. However, we did find that Irf-7-deficient mice had impaired acquired resistance to hepatic L. donovani infection. This phenotype was attributable to a reduction in the capacity of hepatic CD4(+) T cells, NK cell and NKT cells to produce IFNγ and also to defective induction of NOS2 in infected Kupffer cells. Our data therefore add Irf-7 to the growing list of interferon regulatory factors that have effects on downstream events in the acquired cellular immune response to non-viral pathogens.
	PMID: 21149596 [PubMed - as supplied by publisher]