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Sent on Friday, 2011 Oct 14Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Metallomics. 2011 Oct 13. [Epub ahead of print]Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo.Fuad FA, Fothergill-Gilmore LA, Nowicki MW, Eades LJ, Morgan HP, McNae IW, Michels PA, Walkinshaw MD.SourceStructural Biochemistry Group, Institute of Structural and Molecular Biology, University of Edinburgh, Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh, UKEH9 3JR. AbstractProduction of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus Trypanosoma is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co(2+) to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form T. brucei (analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg(2+), Zn(2+) and Fe(2+) were the most abundant, whereas Co(2+) was below the limit of detection (<0.035 μM). The low concentration indicates that Co(2+) is unlikely to be the biologically relevant metal, but that instead, Mg(2+) and/or Zn(2+) may assume this role. Results from metal analysis of purified Leishmania mexicana iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg(2+) and Zn(2+), and are consistent with this proposal. Our data suggest that in vivo cellular conditions lacking Co(2+) are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg(2+) and/or Zn(2+). The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies. |
| 2. | Global Health. 2011 Oct 12;7(1):39. [Epub ahead of print]A win-win solution?: A critical analysis of tiered pricing to improve access to medicines in developing countries.Moon S, Jambert E, Childs M, von Schoen-Angerer T.AbstractABSTRACT: BACKGROUND:Tiered pricing - the concept of selling drugs and vaccines in developing countries at prices systematically lower than in industrialized countries - has received widespread support from industry, policymakers, civil society, and academics as a way to improve access to medicines for the poor. We carried out case studies based on a review of international drug price developments for antiretrovirals, artemisinin combination therapies, drug-resistant tuberculosis medicines, liposomal amphotericin B (for visceral leishmaniasis), and pneumococcal vaccines. DISCUSSION:We found several critical shortcomings to tiered pricing: it is inferior to competition for achieving the lowest sustainable prices; it often involves arbitrary divisions between markets and/or countries, which can lead to very high prices for middle-income markets; and it leaves a disproportionate amount of decision-making power in the hands of sellers vis-a-vis consumers. In many developing countries, resources are often stretched so tight that affordability can only be approached by selling medicines at or near the cost of production. Policies that "de-link" the financing of R&D from the price of medicines merit further attention, since they can reward innovation while exploiting robust competition in production to generate the lowest sustainable prices. However, in special cases - such as when market volumes are very small or multi-source production capacity is lacking - tiered pricing may offer the only practical option to meet short-term needs for access to a product. In such cases, steps should be taken to ensure affordability and availability in the longer-term. SUMMARY:To ensure access to medicines for populations in need, alternate strategies should be explored that harness the power of competition, avoid arbitrary market segmentation, and/or recognize government responsibilities. Competition should generally be the default option for achieving affordability, as it has proven superior to tiered pricing for reliably achieving the lowest sustainable prices. |
| 3. | Ethiop Med J. 2011 Jul;49(3):179-86.Serum chemokine profiles in visceral leishmaniasis, HIV and HIV/ visceral leishmaniasis co-infected Ethiopian patients.Sisay Z, Berhe N, Petros B, Tegbaru B, Messele T, Hailu A, Wolday D.SourceAklilu Lemma Institute of Pathobiology, Addis Ababa University, P. o. Box 1176. AbstractBACKGROUND:The search for a correlation between chemokine levels in plasma or serum and protection from HIV infection or progression to AIDS has been attempted by a number of workers. Chemokines are also suggested to play a role in immunity to Leishmania and Leishmania co-infection with HIV. OBJECTIVE:To assess plasma level of alpha chemokine (CXCL12, formerly known as SDF-1alpha) and beta chemokines (CCL3, CCL4 and CCL5, formerly known as MIP-1alpha, MIP-1beta and RANTES, respectively) in HIV Visceral Leishmaniasis (VL) and HIV/VL coinfection. METHODS:Frozen serum samples from a cross sectional study were used. The samples (n = 80) were comprised of healthy controls (n = 20), HIV patients (n = 20); Visceral Leishmaniasis (VL) patients (n = 22), and HIV/VL coinfected patients (n = 18). Chemokine levels of MIP-1alpha, MIP-1beta, RANTES, and SDF-1alpha of the serum samples were determined using ELISA. RESULTS:MIP-1alpha and MIP-1beta expression were significantly elevated in Leishmania infected (p < 0.001) and in HIV/ VL co-infected individuals (p < 0.001) as compared to the control groups, while no significant difference was seen between HIV infected patients p > 0.05, implying that VL alone might modulate the production of these two chemokines in the case of co-infection In RANTES, however, its expression was significantly higher in HIV patients compared to controls (p = 0.002). Further assessment of serum RANTES concentration in HIV patients has shown a tendency of negative association with viral load. Higher amount of the alpha chemokine, SDF-1alpha, was detected in the HIV patients (p = 0.001) than the control group. Also a trend of positive association between SDF-1alpha and CD4 count was observed CONCLUSION:From our data we can speculate that RANTES and SDF-1alpha might be involved in the regulation of HIV; and MIP-1alpha and MIP-1beta in VL. Therefore, enhancing or suppressing the production of these chemokines might help in therapeutic intervention of VL or HIV. |
| 4. | J Infect Dis. 2011 Sep;204(6):951-61.Host cell lipid bodies triggered by Trypanosoma cruzi infection and enhanced by the uptake of apoptotic cells are associated with prostaglandin E₂ generation and increased parasite growth.D'Avila H, Freire-de-Lima CG, Roque NR, Teixeira L, Barja-Fidalgo C, Silva AR, Melo RC, Dosreis GA, Castro-Faria-Neto HC, Bozza PT.SourceLaboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. AbstractLipid bodies (lipid droplets) are lipid-rich organelles with functions in cell metabolism and signaling. Here, we investigate the mechanisms of Trypanosoma cruzi-induced lipid body formation and their contributions to host-parasite interplay. We demonstrate that T. cruzi-induced lipid body formation in macrophages occurs in a Toll-like receptor 2-dependent mechanism and is potentiated by apoptotic cell uptake. Lipid body biogenesis and prostaglandin E₂ (PGE₂) production triggered by apoptotic cell uptake was largely dependent of α(v)β₃ and transforming growth factor-β signaling. T. cruzi-induced lipid bodies act as sites of increased PGE synthesis. Inhibition of lipid body biogenesis by the fatty acid synthase inhibitor C75 reversed the effects of apoptotic cells on lipid body formation, eicosanoid synthesis, and parasite replication. Our findings indicate that lipid bodies are highly regulated organelles during T. cruzi infection with roles in lipid mediator generation by macrophages and are potentially involved in T. cruzi-triggered escape mechanisms. |
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| 5. | PLoS Comput Biol. 2011 Jun;7(6):e1002058. Epub 2011 Jun 16.Impact of microscopic motility on the swimming behavior of parasites: straighter trypanosomes are more directional.Uppaluri S, Nagler J, Stellamanns E, Heddergott N, Herminghaus S, Engstler M, Pfohl T.SourceMax-Planck-Institute for Dynamics and Self-Organization, Göttingen, Germany. AbstractMicroorganisms, particularly parasites, have developed sophisticated swimming mechanisms to cope with a varied range of environments. African Trypanosomes, causative agents of fatal illness in humans and animals, use an insect vector (the Tsetse fly) to infect mammals, involving many developmental changes in which cell motility is of prime importance. Our studies reveal that differences in cell body shape are correlated with a diverse range of cell behaviors contributing to the directional motion of the cell. Straighter cells swim more directionally while cells that exhibit little net displacement appear to be more bent. Initiation of cell division, beginning with the emergence of a second flagellum at the base, correlates to directional persistence. Cell trajectory and rapid body fluctuation correlation analysis uncovers two characteristic relaxation times: a short relaxation time due to strong body distortions in the range of 20 to 80 ms and a longer time associated with the persistence in average swimming direction in the order of 15 seconds. Different motility modes, possibly resulting from varying body stiffness, could be of consequence for host invasion during distinct infective stages. |
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