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Sent on Tuesday, 2012 May 01Search: kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Anemia. 2012;2012:707402. Epub 2012 Apr 1.Cobalamin and folic Acid status in relation to the etiopathogenesis of pancytopenia in adults at a tertiary care centre in north India.Premkumar M, Gupta N, Singh T, Velpandian T.SourceDepartment of Medicine, Maulana Azad Medical College and Associated Hospitals, Bahadur Shah Zafar Marg, New Delhi 110002, India. AbstractBackground. Pancytopenia has multiple etiologies like megaloblastic anemia, aplastic anemia, leukemia, and various infections. We investigated the clinical, etiological and hematological profile including bone marrow morphology of patients with pancytopenia in relation to their vitamin B12 and folic acid status at a tertiary care referral hospital in north India. Methods. A total of 140 consecutive patients with pancytopenia were selected from June 2007 to December 2008. Bone marrow examination and other tests were carried out as warranted, including serum cobalamin and folate assays using liquid chromatography mass spectroscopy (LC MS/MS). Results. The study population consisted of 92 males and 48 females with a mean age of 32.8 years. Megaloblastic anemia 60.7%, aplastic anemia (7.8%), and leukemia (9.2%) were common causes. Infectious causes (16.4% of all cases) included leishmaniasis, HIV-AIDS, malaria and tuberculosis. Severe cobalamin deficiency (B12 < 100 pg/mL) was seen in 81% of all patients including 91.6% of patients with MA. In contrast, only 7.14% of all pancytopenic patients were folate deficient. Folate deficiency (<5 ng/mL) was seen in just 5% MA patients. Combined cobalamin and folate deficiency was seen in 5 patients (3.51%). Conclusion. Cobalamin deficiency was found to be more common in our setting and is largely underdiagnosed in the age of folate supplementation. Infectious diseases like tuberculosis, leishmaniasis, and increasingly HIV are important and treatable causes of pancytopenia. This is in contrast with the developed nations where the bulk of disease is due to malignancy or marrow aplasia. |
| PMID: 22545211 [PubMed - in process] | |
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| 2. | PLoS Negl Trop Dis. 2012 Apr;6(4):e1627. Epub 2012 Apr 24.Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species.Rodriguez-Pinto D, Navas A, Blanco VM, Ramírez L, Garcerant D, Cruz A, Craft N, Saravia NG.SourceCentro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia. AbstractBACKGROUND:The inflammatory response is prominent in the pathogenesis of dermal leishmaniasis. We hypothesized that regulatory T cells (Tregs) may be diminished in chronic dermal leishmaniasis (CDL) and contribute to healing during treatment. METHODOLOGY/PRINCIPAL FINDINGS:The frequency and functional capacity of Tregs were evaluated at diagnosis and following treatment of CDL patients having lesions of ≥6 months duration and asymptomatically infected residents of endemic foci. The frequency of CD4(+)CD25(hi) cells expressing Foxp3 or GITR or lacking expression of CD127 in peripheral blood was determined by flow cytometry. The capacity of CD4(+)CD25(+) cells to inhibit Leishmania-specific responses was determined by co-culture with effector CD4(+)CD25(-) cells. The expression of FOXP3, IFNG, IL10 and IDO was determined in lesion and leishmanin skin test site biopsies by qRT-PCR. Although CDL patients presented higher frequency of CD4(+)CD25(hi)Foxp3(+) cells in peripheral blood and higher expression of FOXP3 at leishmanin skin test sites, their CD4(+)CD25(+) cells were significantly less capable of suppressing antigen specific-IFN-γ secretion by effector cells compared with asymptomatically infected individuals. At the end of treatment, both the frequency of CD4(+)CD25(hi)CD127(-) cells and their capacity to inhibit proliferation and IFN-γ secretion increased and coincided with healing of cutaneous lesions. IDO was downregulated during healing of lesions and its expression was positively correlated with IFNG but not FOXP3. CONCLUSIONS/SIGNIFICANCE:The disparity between CD25(hi)Foxp3(+) CD4 T cell frequency in peripheral blood, Foxp3 expression at the site of cutaneous responses to leishmanin, and suppressive capacity provides evidence of impaired Treg function in the pathogenesis of CDL. Moreover, the concurrence of increased Leishmania-specific suppressive capacity with induction of a CD25(hi)CD127(-) subset of CD4 T cells during healing supports the participation of Tregs in the resolution of chronic dermal lesions. Treg subsets may therefore be relevant in designing immunotherapeutic strategies for recalcitrant dermal leishmaniasis caused by Leishmania (Viannia) species. |
| PMID: 22545172 [PubMed - as supplied by publisher] | |
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| 3. | PLoS Negl Trop Dis. 2012 Apr;6(4):e1625. Epub 2012 Apr 24.Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs.Bell AS, Mills JE, Williams GP, Brannigan JA, Wilkinson AJ, Parkinson T, Leatherbarrow RJ, Tate EW, Holder AA, Smith DF.SourceWorldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Kent, United Kingdom. AbstractInhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. |
| PMID: 22545171 [PubMed - as supplied by publisher] | |
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| 4. | J Trop Med. 2012;2012:340538. Epub 2012 Mar 27.Towards Point-of-Care Diagnostic and Staging Tools for Human African Trypanosomiaisis.Matovu E, Kazibwe AJ, Mugasa CM, Ndungu JM, Njiru ZK.SourceSchool of Veterinary Medicine, Makerere University, P.O. Box 7062, Kampala, Uganda. AbstractHuman African trypanosomiasis is a debilitating disease prevalent in rural sub-Saharan Africa. Control of this disease almost exclusively relies on chemotherapy that should be driven by accurate diagnosis, given the unacceptable toxicity of the few available drugs. Unfortunately, the available diagnostics are characterised by low sensitivities due to the inherent low parasitaemia in natural infections. Demonstration of the trypanosomes in body fluids, which is a prerequisite before treatment, often follows complex algorithms. In this paper, we review the available diagnostics and explore recent advances towards development of novel point-of-care diagnostic tests. |
| PMID: 22545057 [PubMed - in process] | |
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| 5. | Appl Environ Microbiol. 2012 Apr 27. [Epub ahead of print]Microfauna-host interactions: implications for trypanosome transmission dynamics in Glossina fuscipes fuscipes in Uganda.Alam U, Hyseni C, Symula RE, Brelsfoard C, Wu Y, Kruglov O, Wang J, Echodu R, Alioni V, Okedi LM, Caccone A, Aksoy S.SourceYale University School of Public Health, LEPH 626, 60 College Street, New Haven, Connecticut 06520, USA. AbstractTsetse flies (Diptera Glossinidae) vector African trypanosomes (Euglenozoa: kinetoplastida), protozoan parasites that cause African trypanosomiasis in humans (HAT) and nagana in livestock. In addition to trypanosomes, two symbiotic bacteria (Wigglesworthia glossinidia and Sodalis glossinidius) and two parasitic microbes, Wolbachia and a Salivary Gland Hypertrophy Virus (SGHV) have been described in tsetse. Here we determined the prevalence and co-infection dynamics between Wolbachia, trypanosomes and SGHV in Glossina fuscipes fuscipes (Gff) in Uganda over a large geographical scale spanning the range of host genetic and spatial diversity. Using a multivariate analysis approach, we uncovered complex co-infection dynamics between the pathogens and statistically significant associations between host genetic groups and pathogen prevalence. It is important to note these co-infection dynamics and associations with host were not apparent by univarient analysis. These associations are particularly evident for Wolbachia and SGHV where host groups are inversely correlated for Wolbachia and SGHV prevalence. On the other hand, trypanosome infection prevalence is more complex and covaries with the presence of the other two pathogens, highlighting the importance of examining multiple pathogens simultaneously before making generalizations about infection and spatial patterns. It is imperative to note that these novel findings would have been missed if we had employed standard univariate analysis used in previous studies. Our results are discussed in the context of disease epidemiology and vector control. |
| PMID: 22544247 [PubMed - as supplied by publisher] | |
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| 6. | Amino Acids. 2012 Apr 29. [Epub ahead of print]Enhanced leishmanicidal activity of cryptopeptide chimeras from the active N1 domain of bovine lactoferrin.Silva T, Abengózar MA, Fernández-Reyes M, Andreu D, Nazmi K, Bolscher JG, Bastos M, Rivas L.SourceDepartamento de Química e Bioquímica, Faculdade de Ciências, Centro Investigação em Química CIQ(UP), Universidade do Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal. AbstractTwo antimicrobial cryptopeptides from the N1 domain of bovine lactoferrin, lactoferricin (LFcin17-30) and lactoferrampin (LFampin265-284), together with a hybrid version (LFchimera), were tested against the protozoan parasite Leishmania. All peptides were leishmanicidal against Leishmania donovani promastigotes, and LFchimera showed a significantly higher activity over its two composing moieties. Besides, it was the only peptide active on Leishmania pifanoi axenic amastigotes, already showing activity below 10 μM. To investigate their leishmanicidal mechanism, promastigote membrane permeabilization was assessed by decrease of free ATP levels in living parasites, entrance of the vital dye SYTOX Green (MW = 600 Da) and confocal and transmission electron microscopy. The peptides induced plasma membrane permeabilization and bioenergetic collapse of the parasites. To further clarify the structural traits underlying the increased leishmanicidal activity of LFchimera, the activity of several analogues was assessed. Results revealed that the high activity of these hybrid peptides seems to be related to the order and sequence orientation of the two cryptopeptide moieties, rather than to their particular linkage through an additional lysine, as in the initial LFchimera. The incorporation of both antimicrobial cryptopeptide motifs into a single linear sequence facilitates chemical synthesis and should help in the potential clinical application of these optimized analogues. |
| PMID: 22543751 [PubMed - as supplied by publisher] | |
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| 7. | Trop Biomed. 2012 Mar;29(1):1-8.First molecular detection of Leishmania major within naturally infected Phlebotomus salehi from a zoonotic cutaneous leishmaniasis focus in southern Iran.Azizi K, Fakoorziba MR, Jalali M, Moemenbellah-Fard MD.SourceDepartment of Medical Entomology, School of Health and Nutrition, Research Centre for Health Sciences, Shiraz University of Medical Sciences, P.O. Box: 71645-111, Shiraz, Iran. AbstractHuman cutaneous leishmaniasis (CL) is a major notifiable public health problem in many parts of Iran. It is often caused by the zooflagellate parasite Leishmania major which is mainly transmitted by the bites of female phlebotomine sandflies belonging to the genus Phlebotomus (Diptera: Psychodidae). The annual incidence of CL in Fars province, southern Iran, was about 108-144 in 2007. The leishmanial infections of wild sandflies that may act as vectors were thus investigated at an endemic focus in this province. In all 330 female Phlebotomus sandflies were screened for the detection of Leishmania-specific kinetoplast DNA (kDNA) by polymerase chain reaction (PCR) methods. A two stage nested PCR protocol was used to establish the identity of Leishmania major species in naturally infected sandflies. The L. major kDNA was detected in 18 (5.5%) individual sandflies which belonged to four different Phlebotomus species (Phlebotomus papatasi, Phlebotomus salehi, Phlebotomus sergenti and P. major group). For the first time, one naturally infected P. salehi specimen contained the kDNA of the protozoan parasite, L. major, with a main band of 560 base pairs identified using the nested PCR method. It seems most likely therefore that P. salehi is potentially a rare sylvatic vector of L. major parasites in parts of this province. This is the first combined morphological and molecular studies of P. salehi in Iran. |
| PMID: 22543597 [PubMed - in process] | |
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| 8. | Nat Rev Microbiol. 2012 Apr 30. doi: 10.1038/nrmicro2779. [Epub ahead of print]Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act.Macgregor P, Szöőr B, Savill NJ, Matthews KR.SourceCentre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, United Kingdom. AbstractDuring their life cycle, trypanosomes must overcome conflicting demands to ensure their survival and transmission. First, they must evade immunity without overwhelming the host. Second, they must generate and maintain transmission stages at sufficient levels to allow passage into their tsetse vector. Finally, they must rapidly commit to onward development when they enter the tsetse fly. On the basis of recent quantification and modelling of Trypanosoma brucei infection dynamics, we propose that the interplay between immune evasion and development achieves both infection chronicity and transmissibility. Moreover, we suggest that a novel form of bistable regulation ensures developmental commitment on entry into the tsetse fly midgut. |
| PMID: 22543519 [PubMed - as supplied by publisher] | |
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| 9. | Biochimie. 2012 Apr 21. [Epub ahead of print]Crystal structure of dihydroorotate dehydrogenase from Leishmania major.Cordeiro AT, Feliciano PR, Pinheiro MP, Nonato MC.SourceLaboratório de Cristalografia de Proteínas, Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. Café S/N, Monte Alegre, Ribeirão Preto 14040-903, S.P, Brazil. AbstractDihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and has been exploited as the target for therapy against proliferative and parasitic diseases. In this study, we report the crystal structures of DHODH from Leishmania major, the species of Leishmania associated with zoonotic cutaneous leishmaniasis, in its apo form and in complex with orotate and fumarate molecules. Both orotate and fumarate were found to bind to the same active site and exploit similar interactions, consistent with a ping-pong mechanism described for class 1A DHODHs. Analysis of LmDHODH structures reveals that rearrangements in the conformation of the catalytic loop have direct influence on the dimeric interface. This is the first structural evidence of a relationship between the dimeric form and the catalytic mechanism. According to our analysis, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to validate DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping sickness and Chagas' diseases. Copyright © 2012 Elsevier Masson SAS. All rights reserved. |
| PMID: 22542640 [PubMed - as supplied by publisher] | |
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| 10. | J Inorg Biochem. 2012 Mar 4;112C:1-9. [Epub ahead of print]In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis.Ramírez-Macías I, Maldonado CR, Marín C, Olmo F, Gutiérrez-Sánchez R, Rosales MJ, Quirós M, Salas JM, Sánchez-Moreno M.SourceDepartamento de Parasitología, Universidad de Granada, 18071 Granada, Spain. AbstractStudies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death. Copyright © 2012 Elsevier Inc. All rights reserved. |
| PMID: 22542591 [PubMed - as supplied by publisher] | |
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