Friday, April 17, 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: Cochrane Database Syst Rev. 2009 Apr 15;(2):CD004834.Click here to read

Interventions for American cutaneous and mucocutaneous leishmaniasis.

González U, Pinart M, Rengifo-Pardo M, Macaya A, Alvar J, Tweed JA.

Department of Dermatology, Research Unit for Evidence-based Dermatology, Hospital Plató, c/ Plato 21, Barcelona, Catalunya, Spain, 08006.

BACKGROUND: Pentavalent antimonial drugs are the most prescribed treatment for American cutaneous and mucocutaneous leishmaniasis. Other drugs have been used with varying success. OBJECTIVES: To assess the effects of therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (January 2009), the Register of Controlled Clinical Trials in The Cochrane Library (Issue 1,2009), MEDLINE (2003 to January 2009), EMBASE (2005 to January 2009), LILACS (from inception to January 2009), CINAHL (1982-May 2007) and other databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing treatments for American cutaneous and mucocutaneous leishmaniasis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: We included 38 trials involving 2728 participants. Results are based on individual studies or limited pooled analyses. There was good evidence in:Leishmania braziliensis and L. panamensis infections:Intramuscular (IM) meglumine antimoniate (MA) was better than oral allopurinol for 28 days (1RCT n=127, RR 0.39; 95% CI 0.26, 0.58). Intravenous (IV)MA for 20-days was better than 3-day and 7-day IVMA plus 15% paromomycin plus 12% methylbenzethonium chloride (PR-MBCL) or 7-day IVMA (1RCT n= 150, RR 0.24; 95% CI 0.11, 0.50; RR 0.69; 95% CI 0.53, 0.90; RR 0.64; 95% CI 0.44, 0.92 respectively). Oral allopurinol plus antimonials was better than IV antimonials (2RCT n= 168, RR 1.90; 95% CI 1.40, 2.59; I(2)=0%).L. braziliensis infections:Oral pentoxifylline plus IV sodium stibogluconate (SSG) was better than IVSSG (1RCT n= 23, RR 1.66; 95% CI 1.03, 2.69); IVMA was better than IM aminosidine sulphate (1RCT n= 38, RR 0.05; 95% CI 0.00, 0.78) and better than IV pentamidine isethionate (1RCT n= 80, RR 0.45; 95% CI 0.29, 0.71). Intramuscular MA was better than Bacillus Calmette-Guérin (1RCT n= 93, RR 0.46; 95% CI 0.32, 0.65).L .panamensis infections:Oral allopurinol was better than IVMA (1RCT n= 58, RR 2.20; 95% CI 1.34, 3.60). Aminosidine sulphate at doses of 12mg/kg/day and 18mg/kg/day for 14 days were better than aminosidine sulphate 12mg/kg/day for 7 days (1RCT n= 60, RR 0.23; 95% CI 0.07, 0.73; RR 0.23; 95% CI 0.07, 0.73 respectively). Oral ketoconazole for 28 days, oral miltefosine and topical PR-MBCL were better than placebo. AUTHORS' CONCLUSIONS: Most trials have been designed and reported so poorly that they are inconclusive. There is a need for large well conducted studies that evaluate long-term effects of current therapies to improve quality and standardization of methods.

PMID: 19370612 [PubMed - in process]

Patient Drug Information

  • Allopurinol (Aloprim® , Zyloprim® )

    Allopurinol is used to treat gout, high levels of uric acid in the body caused by certain cancer medications, and kidney stones. Allopurinol is in a class of medications called xanthine oxidase inhibitors. It works by re...

  • Ketoconazole (Nizoral® )

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  • Source: AHFS Consumer Medication Information
2: J Comput Aided Mol Des. 2009 Apr 16. [Epub ahead of print]Click here to read

Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design.

Sheng C, Ji H, Miao Z, Che X, Yao J, Wang W, Dong G, Guo W, Lü J, Zhang W.

School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, 200433, Shanghai, People's Republic of China.

Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.

PMID: 19370313 [PubMed - as supplied by publisher]

3: Nature. 2009 Apr 15. [Epub ahead of print]Click here to read

A yeast-endonuclease-generated DNA break induces antigenic switching in Trypanosoma brucei.

Boothroyd CE, Dreesen O, Leonova T, Ly KI, Figueiredo LM, Cross GA, Papavasiliou FN.

[1] Laboratory of Lymphocyte Biology, and, [2] These authors contributed equally to this work.

Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of the causes of nagana in cattle. This protozoan parasite evades the host immune system by antigenic variation, a periodic switching of its variant surface glycoprotein (VSG) coat. VSG switching is spontaneous and occurs at a rate of about 10(-2)-10(-3) per population doubling in recent isolates from nature, but at a markedly reduced rate (10(-5)-10(-6)) in laboratory-adapted strains. VSG switching is thought to occur predominantly through gene conversion, a form of homologous recombination initiated by a DNA lesion that is used by other pathogens (for example, Candida albicans, Borrelia sp. and Neisseria gonorrhoeae) to generate surface protein diversity, and by B lymphocytes of the vertebrate immune system to generate antibody diversity. Very little is known about the molecular mechanism of VSG switching in T. brucei. Here we demonstrate that the introduction of a DNA double-stranded break (DSB) adjacent to the approximately 70-base-pair (bp) repeats upstream of the transcribed VSG gene increases switching in vitro approximately 250-fold, producing switched clones with a frequency and features similar to those generated early in an infection. We were also able to detect spontaneous DSBs within the 70-bp repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DSB by break-induced replication.

PMID: 19369939 [PubMed - as supplied by publisher]

4: Genes Dev. 2009 Apr 15. [Epub ahead of print]Click here to read

Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei.

Siegel TN, Hekstra DR, Kemp LE, Figueiredo LM, Lowell JE, Fenyo D, Wang X, Dewell S, Cross GA.

Laboratory of Molecular Parasitology, The Rockefeller University, New York, New York 10065, USA;

Unusually for a eukaryote, genes transcribed by RNA polymerase II (pol II) in Trypanosoma brucei are arranged in polycistronic transcription units. With one exception, no pol II promoter motifs have been identified, and how transcription is initiated remains an enigma. T. brucei has four histone variants: H2AZ, H2BV, H3V, and H4V. Using chromatin immunoprecipitation (ChIP) and sequencing (ChIP-seq) to examine the genome-wide distribution of chromatin components, we show that histones H4K10ac, H2AZ, H2BV, and the bromodomain factor BDF3 are enriched up to 300-fold at probable pol II transcription start sites (TSSs). We also show that nucleosomes containing H2AZ and H2BV are less stable than canonical nucleosomes. Our analysis also identifies >60 unexpected TSS candidates and reveals the presence of long guanine runs at probable TSSs. Apparently unique to trypanosomes, additional histone variants H3V and H4V are enriched at probable pol II transcription termination sites. Our findings suggest that histone modifications and histone variants play crucial roles in transcription initiation and termination in trypanosomes and that destabilization of nucleosomes by histone variants is an evolutionarily ancient and general mechanism of transcription initiation, demonstrated in an organism in which general pol II transcription factors have been elusive.

PMID: 19369410 [PubMed - as supplied by publisher]

5: Vet Parasitol. 2009 Mar 26. [Epub ahead of print]Click here to read

Canine leishmaniosis in the United Kingdom: A zoonotic disease waiting for a vector?

Shaw SE, Langton DA, Hillman TJ.

Department of Clinical Veterinary Science, University of Bristol, Langford House, Langford, North Somerset BS40 5DU, UK.

Leishmaniosis is an important sand fly transmitted protozoan disease of dogs and humans. In northern Europe, infection is mainly restricted to dogs that have travelled to and/or from endemic areas of the Mediterranean region during periods when there is high sand fly exposure, mostly between March and November. Infected dogs in these areas in northern latitudes are a potential reservoir should incursion of a competent vector occur. However, information on the scale of the potential reservoir in the UK is lacking. Confirmed cases of canine leishmaniosis entering the United Kingdom between 2005 and 2007 were identified using diagnostic samples submitted to the Department of Clinical Veterinary Science, University of Bristol and from collaborating laboratories (n=257). All study dogs had clinico-pathological signs compatible with leishmaniosis, as typically reported in endemic countries and were leishmania positive in real time or conventional PCR tests, IFA serology and/or tissue microscopic examination for amastigote identification. Information obtained from each case included travel history, habitat, clinico-pathological findings and geographical location once located in the UK. The majority of dogs with complete travel history (n=183) had spent at least 6 months in Spain (105/183), 28/183 were rescued from re-homing centres in the country of origin and 26/183 entered the UK with confirmed leishmaniosis. Once located in the UK, the majority of positive cases were resident in south and central England. The spectrum of clinico-pathological signs for this group of dogs is similar to that reported in endemic countries. These data confirm that a potentially significant reservoir of infected dogs is resident in areas where future climatic conditions may support introduction of competent vectors.

PMID: 19369005 [PubMed - as supplied by publisher]

6: J Zoo Wildl Med. 2009 Mar;40(1):91-4.

Evidence of Leishmania spp. antibodies and DNA in bush dogs (Speothos venaticus) in Brazil.

Lima VM, Fattori KR, Michelin Ade F, Nogueira Fdos S, Souza Lde O.

Departamento de Clínica, Cirurgia e Reprodução Animal, Faculdade de Odontologia-Medicina Veterinária, Universidade Estadual Paulista, Rua Clóvis Pestana, Araçatuba, São Paulo, Brazil. vmflima@fmva.unesp.br

The municipality of Ilha Solteira, São Paulo, Brazil is an endemic area of leishmaniasis. At the Companhia Energética de São Paulo (CESP) Wild Animal Center of Ilha Solteira, two bush dogs (Speothos venaticus) showed clinical signs of this disease. The amastigote form of Leishmania was detected in lymph-node smears taken by fine-needle biopsy. In addition, serum samples from both animals, screened with an enzyme-linked immunosorbent assay (ELISA), were positive for anti-Leishmania antibodies. Moreover, tissue samples from one of the bush dogs were evaluated for the presence of Leishmania DNA by means of a polymerase chain reaction (PCR). DNA of the parasite was indeed detected in the tissue samples of the liver and the lymph nodes; however, no DNA from the parasite was detected in samples of the skin and spleen. These findings confirm a Leishmania infection in bush dogs (S. venaticus).

PMID: 19368245 [PubMed - in process]

7: Stress. 2009;12(2):144-51.Click here to read LinkOut

Effects of repetitive stress during the acute phase of Trypanosoma cruzi infection on chronic Chagas' disease in rats.

Caetano LC, Brazão V, Filipin Mdel V, Santello FH, Caetano LN, Toldo MP, Caldeira JC, do Prado JC Jr.

Laboratório de Parasitologia, Departamento de Análises Clinicas, Toxicológicas e Bromatológicas, Faculdade de Ciéncias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. leony@fcfrp.usp.br

The effect of repetitive stress during acute infection with Trypanosoma cruzi (T. cruzi) on the chronic phase of ensuing Chagas' disease was the focus of this investigation. The aim of this study was to evaluate in Wistar rats the influence of repetitive stress during the acute phase of infection (7 days) with the Y strain of T. cruzi on the chronic phase of the infection (at 180 days). Exposure to ether vapor for 1 min twice a day was used as a stressor. Repetitive stress enhanced the number of circulating parasites and cardiac tissue disorganization, from a moderate to a severe diffuse mononuclear inflammatory process and the presence of amastigote burden in the cardiac fibers. Immunological parameters revealed that repetitive stress triggered a reduced concanavalin A induced splenocyte proliferation in vitro with major effects on the late chronic phase. Serum interleukin-12 concentration decreased in both stressed and infected rats in the early phase of infection although it was higher on 180 days post-infection. These results suggest that repetitive stress can markedly impair the host's immune system and enhance the pathological process during the chronic phase of Chagas' disease.

PMID: 18850489 [PubMed - indexed for MEDLINE]

8: Parasitol Res. 2009 Jan;104(2):399-410. Epub 2008 Oct 11.Click here to read LinkOut

Geographical clustering of Trypanosoma cruzi I groups from Colombia revealed by low-stringency single specific primer-PCR of the intergenic regions of spliced-leader genes.

Mejía-Jaramillo AM, Arboleda-Sánchez S, Rodríguez IB, Cura C, Salazar A, Del Mazo J, Triana-Chávez O, Schijman AG.

Grupo de Chagas, Universidad de Antioquia, AA 1226 Medellin, Colombia.

A low-stringency single-primer polymerase chain reaction (LSSP-PCR) typing procedure targeted to the intergenic regions of spliced-leader genes (SL) was designed to profile Trypanosoma cruzi I stocks from endemic regions of Colombia. Comparison between SL-LSSP-PCR profiles of parasite DNA from vector faeces and cultures isolated from those faeces showed more conservative signatures than profiles using LSSP-PCR targeted to the minicircle variable regions (kDNA). This was also observed by analysing 15 parasite clones from one stock as well as serial samples of a same stock after in vitro culturing or inoculation into mice. Thus, SL-LSSP-PCR appears more appropriate than kDNA-LSSP-PCR for reliable typing of major T. cruzi I groups from in vitro cultured stocks and triatomine faeces. SL-LSSP-PCR grouped 46 of 47 T. cruzi I Colombian stocks according to their geographical procedences in four clusters: Cluster Cas from Casanare Department, Cluster Mg from Northern Magdalena department, Cluster Mom from Momposina Depression in Southern Magdalena and finally Cluster NW from northwestern Colombia, including Sucre, Chocó, Córdoba and Antioquia departments. Sequence analysis identified punctual mutations among amplicons from each cluster. Within Cluster Mg, sequence polymorphism allowed association with different sylvatic vector species. Novel SL sequences and LSSP-PCR profiles are reported from T. cruzi I infecting Eratyrus cuspidatus, Panstrongylus geniculatus and Rhodnius pallescens vectors.

PMID: 18850114 [PubMed - indexed for MEDLINE]

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