Thursday, May 14, 2009

What's new for 'Trypanosomatids' in PubMed

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Sent on Thursday, 2009 May 14
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 -5 of 5

1: PLoS Pathog. 2009 May;5(5):e1000441. Epub 2009 May 22.Click here to read

Sand fly salivary proteins induce strong cellular immunity in a natural reservoir of visceral leishmaniasis with adverse consequences for leishmania.

Collin N, Gomes R, Teixeira C, Cheng L, Laughinghouse A, Ward JM, Elnaiem DE, Fischer L, Valenzuela JG, Kamhawi S.

Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

Immunity to a sand fly salivary protein protects against visceral leishmaniasis (VL) in hamsters. This protection was associated with the development of cellular immunity in the form of a delayed-type hypersensitivity response and the presence of IFN-gamma at the site of sand fly bites. To date, there are no data available regarding the cellular immune response to sand fly saliva in dogs, the main reservoirs of VL in Latin America, and its role in protection from this fatal disease. Two of 35 salivary proteins from the vector sand fly Lutzomyia longipalpis, identified using a novel approach termed reverse antigen screening, elicited strong cellular immunity in dogs. Immunization with either molecule induced high IgG(2) antibody levels and significant IFN-gamma production following in vitro stimulation of PBMC with salivary gland homogenate (SGH). Upon challenge with uninfected or infected flies, immunized dogs developed a cellular response at the bite site characterized by lymphocytic infiltration and IFN-gamma and IL-12 expression. Additionally, SGH-stimulated lymphocytes from immunized dogs efficiently killed Leishmania infantum chagasi within autologous macrophages. Certain sand fly salivary proteins are potent immunogens obligatorily co-deposited with Leishmania parasites during transmission. Their inclusion in an anti-Leishmania vaccine would exploit anti-saliva immunity following an infective sand fly bite and set the stage for a protective anti-Leishmania immune response.

PMID: 19436732 [PubMed - in process]

2: PLoS Pathog. 2009 May;5(5):e1000436. Epub 2009 May 15.Click here to read

The F(0)F(1)-ATP Synthase Complex Contains Novel Subunits and Is Essential for Procyclic Trypanosoma brucei.

Zíková A, Schnaufer A, Dalley RA, Panigrahi AK, Stuart KD.

Seattle Biomedical Research Institute, Seattle, Washington, United States of America.

The mitochondrial F(0)F(1) ATP synthase is an essential multi-subunit protein complex in the vast majority of eukaryotes but little is known about its composition and role in Trypanosoma brucei, an early diverged eukaryotic pathogen. We purified the F(0)F(1) ATP synthase by a combination of affinity purification, immunoprecipitation and blue-native gel electrophoresis and characterized its composition and function. We identified 22 proteins of which five are related to F(1) subunits, three to F(0) subunits, and 14 which have no obvious homology to proteins outside the kinetoplastids. RNAi silencing of expression of the F(1) alpha subunit or either of the two novel proteins showed that they are each essential for the viability of procyclic (insect stage) cells and are important for the structural integrity of the F(0)F(1)-ATP synthase complex. We also observed a dramatic decrease in ATP production by oxidative phosphorylation after silencing expression of each of these proteins while substrate phosphorylation was not severely affected. Our procyclic T. brucei cells were sensitive to the ATP synthase inhibitor oligomycin even in the presence of glucose contrary to earlier reports. Hence, the two novel proteins appear essential for the structural organization of the functional complex and regulation of mitochondrial energy generation in these organisms is more complicated than previously thought.

PMID: 19436713 [PubMed - in process]

3: PLoS Pathog. 2009 May;5(5):e1000431. Epub 2009 May 15.Click here to read

B7-H1 Blockade Increases Survival of Dysfunctional CD8 T Cells and Confers Protection against Leishmania donovani Infections.

Joshi T, Rodriguez S, Perovic V, Cockburn IA, Stäger S.

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Experimental visceral leishmaniasis (VL) represents an exquisite model to study CD8(+) T cell responses in a context of chronic inflammation and antigen persistence, since it is characterized by chronic infection in the spleen and CD8(+) T cells are required for the development of protective immunity. However, antigen-specific CD8(+) T cell responses in VL have so far not been studied, due to the absence of any defined Leishmania-specific CD8(+) T cell epitopes. In this study, transgenic Leishmania donovani parasites expressing ovalbumin were used to characterize the development, function, and fate of Leishmania-specific CD8(+) T cell responses. Here we show that L. donovani parasites evade CD8(+) T cell responses by limiting their expansion and inducing functional exhaustion and cell death. Dysfunctional CD8(+) T cells could be partially rescued by in vivo B7-H1 blockade, which increased CD8(+) T cell survival but failed to restore cytokine production. Nevertheless, B7-H1 blockade significantly reduced the splenic parasite burden. These findings could be exploited for the design of new strategies for immunotherapeutic interventions against VL.

PMID: 19436710 [PubMed - in process]

4: Ther Clin Risk Manag. 2009 Feb;5(1):117-24. Epub 2009 Mar 26.

A controlled, randomized nonblinded clinical trial to assess the efficacy of amphotericin B deoxycholate as compared to pentamidine for the treatment of antimony unresponsive visceral leishmaniasis cases in Bihar, India.

Das VN, Siddiqui NA, Pandey K, Singh VP, Topno RK, Singh D, Verma RB, Ranjan A, Sinha PK, Das P.

Department of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Patna, Bihar, India;

BACKGROUND: There is significant variation in Amphotericin B (AMB) efficacy and relapses in antimony unresponsive visceral leishmaniasis (VL) cases over a period of time (10-15 years). Keeping in mind the above mentioned view this study was undertaken with an objective to assess the magnitude of cure and relapse rates of AMB in the treatment of antimony unresponsive VL cases. METHODS: In a controlled, randomized nonblinded clinical trial, we evaluated the cure and relapse rate of Amphotericin B deoxycholate as compared to pentamidine. A total of 82 sodium stibogluconate (SSG) unresponsive and parasitologically confirmed VL cases were included in this study and randomized into two groups, test (Amphotericin B) and control (Pentamidine). Both the groups were treated with recommended dosages (as per World Health Organization guidelines) of respective medicines. All the patients were followed up on 1st, 2nd, and 6th month after end of treatment. RESULTS: Apparent cure rate in the Amphotericin B group was found to be 95% (39/41) compared with 83% (34/41) in the Pentamidine group, which shows significant statistical difference (p = 0.05). The ultimate cure rate was found 92% (38/41) in the Amphotericin B group compared to 73% (30/41) in the Pentamidine group, which shows a significant statistical difference (Yates corrected chi-square = 4.42, p = 0.04). Similarly, significant statistical difference was observed in the relapse rate of the Amphotericin group compared to the Pentamidine group (p = 0.03). CONCLUSIONS: AMB may still be the drug of choice in the management of resistant VL cases in Bihar, India. This is due to its consistent apparent cure rate (95%), low relapse rate (2.5%), and cost effectiveness compared with other available antileishmanial drugs. It is a safe drug even in case of pregnancy. Efforts should be taken to form a future strategy so that this drug and coming newer drugs do not meet a similar fate as has happened to SSG and pentamidine over a span of 10-15 years.

PMID: 19436614 [PubMed - in process]

5: Can J Infect Dis Med Microbiol. 2008 Nov;19(6):394-6.

Use of oral miltefosine for cutaneous leishmaniasis in Canadian soldiers returning from Afghanistan.

Keynan Y, Larios OE, Wiseman MC, Plourde M, Ouellette M, Rubinstein E.

Departments of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba.

Old world cutaneous leishmaniasis (CL) is caused by Leishmania major and Leishmania tropica, and is endemic to several Asian and Middle-Eastern countries where the rates of infection can be substantial. CL is one of the most common vector-transmitted parasitic infections in Afghanistan. Six cases of CL in Canadian soldiers returning from Afghanistan are reported in the present study. Their lesions did not improve with fluconazole therapy, and the organism demonstrated in vitro resistance. Oral miltefosine seemed effective.

PMID: 19436567 [PubMed - in process]

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