[leish-l] Fwd: Articles found by RefScout 2005/11/02 2005/44

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This is RefScout-Newsletter 44/2005.






REQUEST: [ leishmaniasis ]

(14 articles match this request. 2 articles matching other requests removed)



PMID: 16258327
 

TITLE: Comparison of the efficacy and pharmacology of formulations of
amphotericin B used in treatment of leishmaniasis.

AUTHORS: Gillian Barratt, Philippe Legrand

AFFILIATION: aCentre of Pharmaceutical Studies, Université Paris XI,
Chatenay-Malabry Cedex, France bPharmaceutical Technology Laboratory,
Université Montpellier I, Montpellier, France.

REFERENCE: Curr Opin Infect Dis 2005 Dec 18(6):527-30

PURPOSE OF REVIEW: Several lipid-based formulations of the antifungal 
and antiparasitic drug amphotericin B are now available on the market. 
The purpose of this review is to assess their efficacy against 
leishmaniasis in both experimental and clinical settings, and to point 
out new developments in the formulation of this antibiotic. RECENT 
FINDINGS: The development of resistance to pentavalent antimony 
compounds has shifted the emphasis to amphotericin B for the treatment 
of visceral leishmaniasis in India. Lipid formulations show good 
efficacy but are expensive. The treatment period with lipid formulations
 is shorter, however, which reduces hospitalization costs. As a result, 
in developed countries where these costs are an important proportion of 
the treatment, lipid formulations are preferred, whereas they remain 
largely inaccessible in developing countries. Lipid-associated 
amphotericin B has been found to be effective for secondary prophylaxis 
in HIV-positive patients, in studies carried out in European countries 
bordering the Mediterranean. SUMMARY: The reduced toxicity of lipid-
based formulations of amphotericin B is no longer in doubt. In India, 
their efficacy against visceral leishmaniasis and shorter treatment 
periods compared with the conventional formulation with deoxycholate has
 to be counter-balanced against the very high cost. By contrast, in 
developed countries around the Mediterranean, where leishmaniasis occurs
 mainly in immunocompromised individuals, lipid formulations have become
 the treatment of choice for visceral disease. The efficacy against 
cutaneous lesions is variable, however, and in some reports oral 
miltefosine was active after failure of treatment with amphotericin B.








PMID: 16236261
 

TITLE: Glyoxalase I from Leishmania donovani: A potential target for
anti-parasite drug.

AUTHORS: Prasad K Padmanabhan, Angana Mukherjee, Sushma Singh, Swati
Chattopadhyaya, Venkataraman S Gowri, Peter J Myler, Narayanaswamy Srinivasan,
Rentala Madhubala

AFFILIATION: School of Life Sciences, Jawaharlal Nehru University, New Delhi
110067, India.

REFERENCE: Biochem Biophys Res Commun 2005 Dec 337(4):1237-48

Glyoxalases are involved in a ubiquitous detoxification pathway. In 
pursuit of a better understanding of the biological function of the 
enzyme, the recombinant glyoxalase I (LdGLOI) protein has been 
characterized from Leishmania donovani, the most important pathogenic 
Leishmania species that is responsible for visceral leishmaniasis. A 
24kDa protein was heterologously expressed in Escherichia coli. LdGLOI 
showed a marked substrate specificity for trypanothione hemithioacetal 
over glutathione hemithioacetal. Antiserum against recombinant LdGLOI 
protein could detect a band of anticipated size approximately 16kDa in 
promastigote extracts. Several inhibitors of human GLOI showed that they
 are weak inhibitors of L. donovani growth. Overexpression of GLOI gene 
in L. donovani using Leishmania expression vector pspalpha hygroalpha, 
we detected elevated expression of GLOI RNA and protein. Comparative 
modelling of the 3-D structure of LDGLOI shows that substrate-binding 
region of the model involves important differences compared to the 
homologues, such as E. coli, specific to glutathione. Most notably a 
substrate-binding loop of LDGLOI is characterized by a deletion of five 
residues compared to the E. coli homologue. Further, a critical Arg in 
the E. coli variant at the substrate-binding site is replaced by Tyr in 
LDGLOI. These major differences result in entirely different shapes of 
the substrate-binding loop and presence of very different chemical 
groups in the substrate-binding site of LDGLOI compared to E. coli 
homologue suggesting an explanation for the difference in the substrate 
specificity. Difference in the substrate specificity of the human and 
LDGLOI enzyme could be exploited for structure-based drug designing of 
selective inhibitors against the parasite.




PMID: 16243129
 

TITLE: Leishmania tropica in northern Israel: a clinical overview of an emerging
focus.

AUTHORS: Ayelet Shani-Adir, Stephanie Kamil, Dganit Rozenman, Eli Schwartz,
Michal Ramon, Lucia Zalman, Abed Nasereddin, Charles L Jaffe, Moshe Ephros

AFFILIATION: Department of Dermatology, Emek Medical Center, Afula, Israel.
adir-sh at zahav.net.il

REFERENCE: J Am Acad Dermatol 2005 Nov 53(5):810-5

BACKGROUND: In Israel, most cutaneous leishmaniasis (CL) is caused by 
Leishmania major. Recently a new focus of CL caused by Leishmania 
tropica has been described in Tiberias and the surrounding area of 
northern Israel. OBJECTIVE: The aim of this study was to evaluate 
clinical (size, number, location, and type of lesion) and laboratory (
culture and polymerase chain reaction [PCR] analysis) parameters at 
diagnosis, response to treatment, and outcome of patients with CL due to
 L tropica. METHODS: Between September 2002 and March 2004, patients 
with direct smear-confirmed CL were evaluated; clinical records were 
reviewed and a telephone survey was performed. RESULTS: Forty nine 
patients, 34 (69%) male and 15 (31%) female, were studied. Mean age was 
31.1 years (median 26 years, range 1-70); 76% of patients live in 
Tiberias and the surrounding area. The mean number of lesions was 2.6 (
median 2, range 1-10). Lesions were commonly located on the face (61%) 
and upper limbs (57%). PCR analysis was performed in 27 patients and was
 positive for L tropica in 26. Fifty percent of patients studied 
received multiple therapeutic regimens because of incomplete response or
 treatment failure. Topical paromomycin was used in 44 patients (90%), 
with a complete response reported in only 17 (39%); of the 9 patients 
treated with intralesional sodium stibogluconate, a complete response 
was reported in 6 (67%); of the 5 patients treated with intravenous 
sodium stibogluconate, 4 (80%) were cured. LIMITATIONS: The relatively 
small number of patients studied combined with the fact that some were 
assessed retrospectively limit our conclusions. In addition, 50% of the 
patients studied received multiple therapeutic regimens because of 
failure of, or incomplete responses to, their initial therapy, thereby 
making comparisons difficult. CONCLUSIONS: The cure rate in those 
completing a course of antimony therapy, either 10 or more days of 
intravenous therapy or therapy administered intralesionally, was 75% (95
% confidence interval [CI], 50.5-99.5%) as compared with 45% (95% CI, 28
.9-60.5%) among those completing at least 10 days of topical paromomycin
. To date, no standardized, simple, safe, and highly effective regimen 
for treating L tropica exists. Large, controlled clinical trials to 
evaluate current treatment regimens as well as new medications for CL, 
and especially CL attributed to L tropica, are urgently needed.




PMID: 16255674
 

TITLE: Clinical status of agents being developed for leishmaniasis.

AUTHORS: Jonathan Berman

AFFILIATION: National Center for Complementary and Alternative Medicine, 6707
Democracy Boulevard, Suite 401, Bethesda MD 20892, USA. bermanjo at mail.nih.gov.

REFERENCE: Expert Opin Investig Drugs 2005 Nov 14(11):1337-46

Leishmaniasis, which exists in both visceral and cutaneous forms, is 
currently treated with intramuscular antimony or intravenous 
amphotericin B. The primary unmet need is for oral therapy. Of the 
several drugs in clinical development, miltefosine is unique in being an
 oral agent with efficacy against both forms of the disease. Sitamaquine
 is an oral agent with substantial but not sufficient efficacy against 
visceral disease. Oral fluconazole has been shown to be more effective 
than placebo in one instance: for Leishmania major cutaneous disease 
from Saudi Arabia. Paromomycin is in widespread trial. Topical 
paromomycin formulations are being tested for cutaneous disease, and 
intramuscular paromomycin is in Phase III trial for Indian visceral 
disease. The most likely replacements for present therapy are oral 
miltefosine for many of the visceral and cutaneous syndromes, 
intramuscular paromomycin for visceral disease and topical paromomycin 
for some forms of cutaneous disease.




PMID: 16239566
 

TITLE: Interleukin-4 (IL-4) and IL-10 collude in vaccine failure for novel
exacerbatory antigens in murine Leishmania major infection.

AUTHORS: Mark T M Roberts, Carmel B Stober, Andrew N McKenzie, Jenefer M
Blackwell

AFFILIATION: Cambridge Institute for Medical Research, Wellcome Trust/MRC
Building, Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2XY, United
Kingdom.

REFERENCE: Infect Immun 2005 Nov 73(11):7620-8

Leishmaniasis affects 12 million people but there are no vaccines in 
routine use. Recently, we used DNA vaccination in a susceptible BALB/c 
high-dose model of infection to screen 100 novel Leishmania major genes 
as vaccine candidates. In addition to finding novel protective antigens
, we identified several antigens that reproducibly exacerbated disease. 
Here we examined the immune response to two of these antigens, lmd29 and
 584C, that were originally identified in an expressed sequence tag cDNA
 sequencing project. We show that, in addition to exacerbating disease 
in susceptible BALB/c mice, these antigens retain a propensity to 
exacerbate disease in resistant C57BL/6 mice. This ability to exacerbate
 disease was lost when susceptible BALB/c mice were rendered resistant 
by disruption of the genes encoding interleukin-4 (IL-4) alone, IL-4/IL-
13, or IL-4, IL-5, IL-9, and IL-13. Failure to exacerbate disease was 
associated with reduced IL-5 and IL-10 production in IL-4 knockout mice
. Treatment of lmd29-vaccinated mice with anti-IL-10 receptor antibody 
prior to challenge infection converted exacerbation in wild-type BALB/c 
mice into highly significant antigen-specific protection. These studies 
demonstrate that some highly immunogenic antigens of L. major, while 
having an intrinsic capacity to exacerbate disease in the context of 
otherwise T helper 1-promoting DNA vaccine delivery, can be rendered 
protective by the removal of functional IL-10.




PMID: 16251285
 

TITLE: Photodynamic Sensitization of Leishmania amazonensis in both
Extracellular and Intracellular Stages with Aluminum Phthalocyanine Chloride
for Photolysis In Vitro.

AUTHORS: Sujoy Dutta, Debalina Ray, Bala K Kolli, Kwang-Poo Chang

AFFILIATION: Chicago Medical School, 3333 Green Bay Rd., N. Chicago, IL 60064.
kwang-poo.chang at rosalindfranklin.edu.

REFERENCE: Antimicrob Agents Chemother 2005 Nov 49(11):4474-84

Leishmania amazonensis, a causative agent of cutaneous leishmaniasis, is
 susceptible in vitro to light-mediated cytolysis in the presence of or 
after pretreatment with the photosensitizer aluminum phthalocyanine 
chloride. Cytolysis of both promastigotes and axenic amastigotes 
required less photosensitizer (e.g., one mug . ml(-1)) and a lower light
 dose (e.g., 1.5 J . cm(-2)) than did the mammalian cells examined for 
comparison. Exposure of Leishmania cells to the photosensitizer alone 
had little effect on their viability, as judged from their motility, 
growth, and/or retention of green fluorescent proteins genetically 
engineered for episomal expression. Fluorimetric assays for cell-
associated and released green fluorescence proteins proved to be even 
more sensitive for the evaluation of cell viability than microscopy for 
the evaluation of motility and/or integrity. Axenic amastigotes 
pretreated with the photosensitizer infected macrophages of the J774 
line but were lysed intracellularly when the infected cells were exposed
 to light. Addition of the photosensitizer to the already infected cells
 produced no effect on their intracellular parasites. However, light 
irradiation lysed these macrophages and also those infected with 
parasites preincubated with the photosensitizer at a concentration of 5 
mug . ml(-1) or higher. Photosensitized Leishmania cells are highly 
susceptible to cytolysis, apparently due to the generation of reactive 
oxidative species on light illumination, suggestive of inefficiency of 
their antioxidant mechanisms. Efficient delivery of photosensitizers to 
intracellular Leishmania is expected to increase their therapeutic 
potentials against leishmaniasis.








PMID: 16251095
 

TITLE: [Dermatologic problems arising during foreign travel]

AUTHORS: Carsten Sand

AFFILIATION: H:S Bispebjerg Hospital, Dermatologisk Afdeling, DK-2400 København
NV. csp01 at bbh.hosp.dk

REFERENCE: Ugeskr Laeger 2005 Oct 167(43):4085-7

The skin is a highly exposed organ during vacation times, especially 
during travel to countries with subtropical and tropical climates. 
Prolonged stay in these countries significantly increases the risk of 
contracting rarely seen dermatoses such as leishmaniasis, larva migrans 
and myiasis. The bites of various flies may provoke itching and 
excoriations that may be infected with Staphylococcus aureus and/or 
hemolytic streptococci, resulting in impetigo, furunculosis or 
erysipelas. Elderly persons spending weeks in the tropical sun may 
develop drug-induced phototoxic or photoallergic rash due to concomitant
 medication for cardiovascular or rheumatic diseases. Acute sunburn is 
considered a short-lasting problem, but in children it increases the 
risk of malignant melanoma in later years. Also of concern is chronic UV
 exposure, which increases the risk of premalignant and malignant skin 
tumors. Finally, mucocutaneous manifestations arising weeks and months 
after returning from vacation should raise suspicions of sexually 
transmitted syphilis and HIV.




PMID: 16223880
 

TITLE: The wound repair response controls outcome to cutaneous leishmaniasis.

AUTHORS: Anuratha Sakthianandeswaren, Colleen M Elso, Ken Simpson, Joan M
Curtis, Beena Kumar, Terence P Speed, Emanuela Handman, Simon J Foote

AFFILIATION: Genetics and Bioinformatics Division and Department of Infection
and Immunity, The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville,
Victoria 3050, Australia.

REFERENCE: Proc Natl Acad Sci U S A 2005 Oct 102(43):15551-6

Chronic microbial infections are associated with fibrotic and 
inflammatory reactions known as granulomas showing similarities to wound
-healing and tissue repair processes. We have previously mapped three 
leishmaniasis susceptibility loci, designated lmr1, -2, and -3, which 
exert their effect independently of T cell immune responses. Here, we 
show that the wound repair response is critically important for the 
rapid cure in murine cutaneous leishmaniasis caused by Leishmania major
. Mice congenic for leishmaniasis resistance loci, which cured their 
lesions more rapidly than their susceptible parents, also expressed 
differentially genes involved in tissue repair, laid down more ordered 
collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast
 monolayers from these mice repaired in vitro wounds faster, and this 
process was accelerated by supernatants from infected macrophages. 
Because these effects are independent of T cell-mediated immunity, we 
conclude that the rate of wound healing is likely to be an important 
component of innate immunity involved in resistance to cutaneous 
leishmaniasis.




PMID: 16247107
 

TITLE: HIV/AIDS and leishmaniasis coinfection in Ethiopia.

AUTHORS: Subhash C Arya, Nirmala Agarwal

REFERENCE: CMAJ 2005 Oct 173(9):1067; author reply 1070




PMID: 16257344
 

TITLE: Advances in leishmaniasis.

AUTHORS: Henry W Murray, Jonathan D Berman, Clive R Davies, Nancy G Saravia

AFFILIATION: Department of Medicine, Weill Medical College of Cornell
University, New York, USA. hwmurray at med.cornell.edu

REFERENCE: Lancet 2005 Oct 29-Nov 4 366(9496):1561-77

Governed by parasite and host factors and immunoinflammatory responses, 
the clinical spectrum of leishmaniasis encompasses subclinical (
inapparent), localised (skin lesions), and disseminated infection (
cutaneous, mucosal, or visceral). Symptomatic disease is subacute or 
chronic and diverse in presentation and outcome. Clinical 
characteristics vary further by endemic region. Despite T-cell-dependent
 immune responses, which produce asymptomatic and self-healing infection
, or appropriate treatment, intracellular infection is probably life-
long since targeted cells (tissue macrophages) allow residual parasites 
to persist. There is an epidemic of cutaneous leishmaniasis in 
Afghanistan and Pakistan and of visceral infection in India and Sudan. 
Diagnosis relies on visualising parasites in tissue or serology; culture
 and detection of parasite DNA are useful in the laboratory. Pentavalent
 antimony is the conventional treatment; however, resistance of visceral
 infection in India has spawned new treatment approaches--amphotericin B
 and its lipid formulations, injectable paromomycin, and oral 
miltefosine. Despite tangible advances in diagnosis, treatment, and 
basic scientific research, leishmaniasis is embedded in poverty and 
neglected. Current obstacles to realistic prevention and proper 
management include inadequate vector (sandfly) control, no vaccine, and 
insufficient access to or impetus for developing affordable new drugs.




PMID: 16164760
 

TITLE: Comparative analysis of the kinomes of three pathogenic trypanosomatids:
Leishmania major, Trypanosoma brucei and Trypanosoma cruzi.

AUTHORS: Marilyn Parsons, Elizabeth A Worthey, Pauline N Ward, Jeremy C Mottram

AFFILIATION: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
marilyn.parsons at sbri.org

REFERENCE: BMC Genomics 2005 Sep 6():127

BACKGROUND: The trypanosomatids Leishmania major, Trypanosoma brucei and
 Trypanosoma cruzi cause some of the most debilitating diseases of 
humankind: cutaneous leishmaniasis, African sleeping sickness, and 
Chagas disease. These protozoa possess complex life cycles that involve 
development in mammalian and insect hosts, and a tightly coordinated 
cell cycle ensures propagation of the highly polarized cells. However, 
the ways in which the parasites respond to their environment and 
coordinate intracellular processes are poorly understood. As a part of 
an effort to understand parasite signaling functions, we report the 
results of a genome-wide analysis of protein kinases (PKs) of these 
three trypanosomatids. RESULTS: Bioinformatic searches of the 
trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs
) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L
. major, most of which are orthologous across the three species. This is
 approximately 30% of the number in the human host and double that of 
the malaria parasite, Plasmodium falciparum. The representation of 
various groups of ePKs differs significantly as compared to humans: 
trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like 
kinases, although they do possess dual-specificity kinases. A relative 
expansion of the CMGC, STE and NEK groups has occurred. A large number 
of unique ePKs show no strong affinity to any known group. The 
trypanosomatids possess few ePKs with predicted transmembrane domains, 
suggesting that receptor ePKs are rare. Accessory Pfam domains, which 
are frequently present in human ePKs, are uncommon in trypanosomatid 
ePKs. CONCLUSION: Trypanosomatids possess a large set of PKs, comprising
 approximately 2% of each genome, suggesting a key role for 
phosphorylation in parasite biology. Whilst it was possible to place 
most of the trypanosomatid ePKs into the seven established groups using 
bioinformatic analyses, it has not been possible to ascribe function 
based solely on sequence similarity. Hence the connection of stimuli to 
protein phosphorylation networks remains enigmatic. The presence of 
numerous PKs with significant sequence similarity to known drug targets
, as well as a large number of unusual kinases that might represent 
novel targets, strongly argue for functional analysis of these molecules.




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PMID: 12837364
 

TITLE: Biflavonoids from Podocalyx loranthoides.

AUTHORS: Alírica I Suárez, Beth Diaz M, Franco Delle Monache, Reinaldo S
Compagnone

AFFILIATION: Facultad de Farmacia, Universidad Central de Venezuela, Caracas,
Venezuela. asuarez at strix.ciens.ucv.ve

REFERENCE: Fitoterapia 2003 Jul 74(5):473-5

Analysis of the ethyl acetate extract of the aerials parts of Podocalyx 
loranthoides led to the isolation of I 7, II 4'-dimethylamentoflavone (1
) and II 4'-methylamentoflavone (2). Compound (1) gave a moderate effect
 against Leishmania mexicana promastigotes.




REQUEST: [ leishmania ]

(20 articles match this request. 8 articles matching other requests removed)







PMID: 16246139
 

TITLE: An in silico analysis of trypanosomatid RNA polymerases: insights into
their unusual transcription.

AUTHORS: S Kelly, B Wickstead, K Gull

AFFILIATION: Sir William Dunn School of Pathology, University of Oxford, South
Parks Road, Oxford OX1 3RE, U.K.

REFERENCE: Biochem Soc Trans 2005 Dec 33(Pt 6):1435-7

African trypanosomes employ both Pol I (RNA polymerase I) and Pol II to 
transcribe protein-coding genes in large polycistronic units of up to 50
 genes. Subsequent processing produces mature capped mRNAs. Evidence 
suggests that regulation of gene expression is primarily exerted post-
transcriptionally. Here, we use the recently completed genome sequences 
of three trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and 
Leishmania major, in an in silico analysis of their fundamental RNA 
polymerase complexes. The core complement of Pol II subunits, including 
those that are shared with Pol I and Pol III are present. However, both 
Pol I and Pol III complexes are missing members of the rpoE-rpoF subunit
 groups. Out of the five shared subunits, both RPB5 and RPB6 have two 
isoforms in the three trypanosomes. One represents the canonical 
polymerase subunit and the other differs by insertion or deletion of 
stretches of charged residues. We propose that these alternative 
isoforms function in distinct polymerase complexes, and may influence 
recruitment of the trypanosome RPB4-RPB7 heterodimer.




PMID: 16143535
 

TITLE: Tannins and related compounds induce nitric oxide synthase and cytokines
gene expressions in Leishmania major-infected macrophage-like RAW 264.7 cells.

AUTHORS: Herbert Kolodziej, Anne Burmeister, Weronika Trun, Oliver A Radtke,
Albrecht F Kiderlen, Hideyuki Ito, Tsutomu Hatano, Takashi Yoshida, Lai Yeap
Foo

AFFILIATION: Institute of Pharmacy, Pharmaceutical Biology, Freie Universität
Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany.

REFERENCE: Bioorg Med Chem 2005 Dec 13(23):6470-6

Some polyphenol-containing extracts (Pelargonium sidoides, Phyllanthus 
amarus) and representatives of simple phenols (shikimic acid 3- and 5-O-
gallate), flavan-3-ols (epigallocatechin 3-gallate), proanthocyanidins (
a hexamer) and hydrolysable tannins (corilagin, casuariin, geraniin) 
were studied for gene expressions (iNOS, IL-1, IL-10, IL-12, IL-18, TNF-
alpha, IFN-alpha/gamma) by RT-PCR. All extracts and compounds were 
capable of enhancing the iNOS and cytokine mRNA levels in parasitised 
cells when compared with those in non-infected conditions.




PMID: 16255743
 

TITLE: Ribavirin up-regulates IL-12 p40 gene expression and restores IL-12
levels in Leishmania-treated PBMCs.

AUTHORS: E Conte, A Modica, B Cacopardo, L Messina, L Nigro, A Messina

AFFILIATION: Department of Biomedical Sciences, Section of General Pathology,
University of Catania, Italy.

REFERENCE: Parasite Immunol 2005 Dec 27(12):447-51

SUMMARY Ribavirin, a nucleoside analogue that interferes with viral mRNA
 synthesis and inhibits the replication of RNA and DNA viruses, has been
 recently proposed as an effective immune response modulator. In the 
present report, we studied the effect of ribavirin on IL-12 p40 gene 
expression in peripheral blood mononuclear cells (PBMCs) of healthy 
subjects. We also studied ribavirin effects on PBMCs activated with 
lipopolysaccharide (LPS) and phytohaemagglutinin (PHA) and treated with 
Leishmania donovani antigens. We provide evidence that ribavirin was 
able to up-regulate IL-12 p40 gene expression and to restore levels of 
IL-12 p40 gene expression and IL-12 secretion in fully activated PBMCs 
that were strongly inhibited by L. donovani antigens. Because effective 
management of leishmanial disease is usually associated with a prevalent
 T-helper 1 immune response with elevated production of IL-12,our 
preliminary results may be of particular interest, provided that they 
will be confirmed by further in vitro and in vivo studies, when 
considering a possible use of ribavirin as adjuvant in severe 
leishmanial disease.




PMID: 16255746
 

TITLE: Modulation of murine cellular immune response and cytokine production by
salivary gland lysate of three sand fly species.

AUTHORS: I Rohousová, P Volf, M Lipoldová

AFFILIATION: Department of Parasitology, Faculty of Science, Charles University
in Prague, Czech Republic.

REFERENCE: Parasite Immunol 2005 Dec 27(12):469-73

SUMMARY Saliva of sand flies (Diptera: Phlebotominae) plays an important
 role in transmission of Leishmania parasites by modulating host immune 
response. However, because of the different protein compositions of 
saliva, the immunomodulatory effects may vary among sand fly species. We
 have therefore analysed and compared the immunomodulation effects of 
salivary gland lysate (SGL) of three different sand flies. Spleen cells 
from BALB/c mice were incubated with SGL of Phlebotomus papatasi, P. 
sergenti or Lutzomyia longipalpis. Concanavalin A-stimulated lymphocyte 
proliferation was significantly suppressed with SGLs of all three sand 
fly species and all SGL doses tested. This result indicates that saliva 
from different sand fly species is able to suppress host proliferative 
response even to the potent mitogen. In parallel experiments, we 
analysed the effect of SGL on IFN-gamma, IL-2, and IL-4 production; in 
mitogen-stimulated cells SGLs markedly inhibited IFN-gamma production in
 all intervals tested (reduced up to 31%) and to a lesser degree 
impaired production of the other two cytokines as well. Despite some 
species-specific differences in the intensity of immunomodulatory 
effects, saliva of all sand fly species modulated cell proliferation as 
well as cytokine production in a similar way.




PMID: 16185885
 

TITLE: Synthesis of chromenochalcones and evaluation of their in vitro
antileishmanial activity.

AUTHORS: Tadigoppula Narender, Tanvir Khaliq, Shweta, Nishi, Neena Goyal, Suman
Gupta

AFFILIATION: Division of Medicinal and Process Chemistry, Central Drug Research
Institute, Lucknow, India.

REFERENCE: Bioorg Med Chem 2005 Dec 13(23):6543-50

A large number of novel chromenochalcones were synthesized by pyridine-
catalysed chromenylation of mono-chelated meta-dihydric acetophenones 
with the monoterpene, citral dimethyl acetal and subsequent Claisen-
Schmidt condensation of the resultant acylchromenes with appropriate 
aromatic aldehydes. These chromenochalcones 1-19 were screened against 
in vitro extracellular promastigotes and intracellular amastigotes of 
Leishmania donovani. The most potent compound in this series was 
compound 9 with a pyridine ring-A, which showed 99% inhibition of 
promastigotes at 10mug/ml, 82% at 0.25mug/ml and 96% at 10mug/ml 
concentration against amastigotes.




PMID: 16126212
 

TITLE: Genomic organization of telomeric and subtelomeric sequences of
Leishmania (Leishmania) amazonensis.

AUTHORS: F F Conte, M I N Cano

AFFILIATION: Departamento de Patologia Clínica, Núcleo de Medicina e Cirurgia
Experimental, Faculdade de Ciências Médicas, Universidade Estadual de
Campinas (UNICAMP), CP 6109, 13083-970, Campinas, SP, Brazil.

REFERENCE: Int J Parasitol 2005 Nov 35(13):1435-43

Telomeres are DNA-protein complexes that protect linear chromosomes from
 degradation and fusions. Telomeric DNA is repetitive and G-rich, and 
protrudes towards the end of the chromosomes as 3'G-overhangs. In 
Leishmania spp., sequences adjacent to telomeres comprise the Leishmania
 conserved telomere associated sequences (LCTAS) that are around 100bp 
long and contain two conserved sequence elements (CSB1 and CSB2), in 
addition to non-conserved sequences. The aim of this work was to study 
the genomic organization of Leishmania (Leishmania) amazonensis 
telomeric/subtelomeric sequences. Leishmania amazonensis chromosomes 
were separated in a single Pulsed Field Gel Electrophoresis (PFGE) gel 
as 25 ethidium bromide-stained bands. All of the bands hybridized with 
the telomeric probe (5'-TTAGGG-3')(3) and with probes generated from the
 conserved subtelomeric elements (CSB1, CSB2). Terminal restriction 
fragments (TRF) of L. amazonensis chromosomes were analyzed by 
hybridizing restriction digested genomic DNA and chromosomal DNA 
separated in 2D-PFGE with the telomeric probe. The L. amazonensis TRF 
was estimated to be approximately 3.3kb long and the telomeres were 
polymorphic and ranged in size from 0.2 to 1.0kb. Afa I restriction 
sites within the conserved CSB1 elements released the telomeres from the
 rest of the chromosome. Bal 31-sensitive analysis confirmed the 
presence of terminal Afa I restriction sites and served to differentiate
 telomeric fragments from interstitial internal sequences. The size of 
the L. amazonensis 3' G-overhang was estimated by non-denaturing 
Southern blotting to be approximately 12nt long. Using similar 
approaches, the subtelomeric domains CSB1 and CSB2 were found to be 
present in a low copy number compared to telomeres and were organized in
 blocks of 0.3-1.5kb flanked by Hinf I and Hae III restriction sites. A 
model for the organization of L. amazonensis chromosomal ends is 
provided.








PMID: 16084646
 

TITLE: Reversible inhibition of contractions of mammalian cardiomyocytes and of
smooth muscle by the protistan parasite Leishmania major.

AUTHORS: R Vaidyanathan

AFFILIATION: Department of Parasitology, The Hebrew University, Hadassah Medical
School, Ein Kerem, Jerusalem 91120, Israel.

REFERENCE: Vet Parasitol 2005 Nov 134(1-2):53-60

Myotropic neuropeptides have been isolated from vertebrates and 
invertebrates. Recently, a myoinhibitory peptide from the protist 
Leishmaniamajor was isolated, and its function in the sand fly vector 
was described. Similar lysates of cultured L. major were tested for 
their ability to inhibit contractions in mammalian cell and tissue 
preparations. L. major proteins (LMP) (34mug/ml) completely stopped 
spontaneous contractions of cultured rat cardiomyocytes; cells resumed 
contracting after a saline wash. An application of 880mug/ml LMP 
significantly decreased force of contractions (36%) in strips of guinea 
pig ileum precontracted with nicotine (p<0.01) but not with 
acetylcholine (p>0.01). Ileal strips rinsed with Tyrode's solution and 
again stimulated with nicotine contracted normally. Contractile force of
 ileal strips electrically stimulated with 40V was reduced in a dose-
dependent manner (30, 76, and 100%) (p<0.01) by increasing 
concentrations of LMP (220, 440, and 880mug/ml). This ileal preparation 
resumed contracting after rinsing with Tyrode's solution. Oxytocin-
induced contractions of guinea pig uterine strips were reduced 
significantly in a dose-dependent manner (21 and 55%) (p<0.01) by 
increasing concentrations (170 and 310mug/ml) of LMP and resumed 
contracting normally after rinsing with Tyrode's solution. Modes of 
action for L. major myoinhibitory factors may include either decreasing 
Ca(2+) influx or increasing Ca(2+) efflux in susceptible muscle. 
Protistan-induced inotropism is discussed in light of exacerbating 
pathology of disease.




PMID: 16199669
 

TITLE: Crystal structures and proposed structural/functional classification of
three protozoan proteins from the isochorismatase superfamily.

AUTHORS: Jonathan Caruthers, Frank Zucker, Elizabeth Worthey, Peter J Myler,
Fred Buckner, Wes Van Voorhuis, Chris Mehlin, Erica Boni, Tiffany Feist, Joseph
Luft, Stacey Gulde, Angela Lauricella, Oleksandr Kaluzhniy, Lori Anderson,
Isolde Le Trong, Margaret A Holmes, Thomas Earnest, Michael Soltis, Keith O
Hodgson, Wim G J Hol, Ethan A Merritt

AFFILIATION: Biomolecular Structure Center M/S 357742, University of Washington,
Seattle, WA 98195, USA. merritt at u.washington.edu.

REFERENCE: Protein Sci 2005 Nov 14(11):2887-94

We have determined the crystal structures of three homologous proteins 
from the pathogenic protozoans Leishmania donovani, Leishmania major, 
and Trypanosoma cruzi. We propose that these proteins represent a new 
subfamily within the isochorismatase superfamily (CDD classification 
cd004310). Their overall fold and key active site residues are 
structurally homologous both to the biochemically well-characterized N-
carbamoylsarcosine-amidohydrolase, a cysteine hydrolase, and to the 
phenazine biosynthesis protein PHZD (isochorismase), an aspartyl 
hydrolase. All three proteins are annotated as mitochondrial-associated 
ribonuclease Mar1, based on a previous characterization of the 
homologous protein from L. tarentolae. This would constitute a new 
enzymatic activity for this structural superfamily, but this is not 
strongly supported by the observed structures. In these protozoan 
proteins, the extended active site is formed by inter-subunit 
association within a tetramer, which implies a distinct evolutionary 
history and substrate specificity from the previously characterized 
members of the isochorismatase superfamily. The characterization of the 
active site is supported crystallographically by the presence of an 
unidentified ligand bound at the active site cysteine of the T. cruzi 
structure.




PMID: 16239557
 

TITLE: Invariant NKT cells are essential for the regulation of hepatic CXCL10
gene expression during Leishmania donovani infection.

AUTHORS: Mattias Svensson, Soombul Zubairi, Asher Maroof, Fatima Kazi, Masaru
Taniguchi, Paul M Kaye

AFFILIATION: Immunology and Infection Unit, Department of Biology, University of
York, Heslington, York YO10 5YW, United Kingdom.

REFERENCE: Infect Immun 2005 Nov 73(11):7541-7

Gamma interferon (IFN-gamma)-regulated chemokines of the CXC family have
 been implicated as key regulators of a variety of T-cell-dependent 
inflammatory processes. However, the cellular source(s) of IFN-gamma 
that regulates their early expression has rarely been defined. Here, we 
have directly addressed this question in mice after Leishmania donovani 
infection. Comparison of CXCL10 mRNA accumulation in normal and IFN-
gamma-deficient mice confirmed an absolute requirement for IFN-gamma for
 sustained (24 h) expression of CXCL10 mRNA accumulation in this model. 
In normal mice, IFN-gamma was produced by both CD3int NK1.1+ NKT cells 
and CD3- NK1.1+ NK cells, as detected by intracellular flow cytometry. 
Strikingly, B6.Jalpha281-/- mice lacking NKT cells that express the 
invariant Valpha14Jalpha18 T-cell-receptor alpha chain, although 
retaining a significant population of IFN-gamma-producing NK cells and 
NKT cells, were unable to sustain CXCL10 mRNA accumulation. These data 
indicate that invariant NKT cells are indispensable for the regulation 
of hepatic CXCL10 gene expression during L. donovani infection.




PMID: 16076527
 

TITLE: Identification of two highly performing Leishmania infantum antigens for
serodiagnosis of canine leishmaniosis.

AUTHORS: M Rami, T Atarhouch, A Dakkak

AFFILIATION: Institut Agronomique et Vétérinaire Hassan II, Department of
Parasitology and Parasitic Diseases, BP 6202, Rabat-Instituts, 10101, Morocco.

REFERENCE: Vet Parasitol 2005 Nov 134(1-2):25-31

In the aim of improving serodiagnosis of canine leishmaniosis, we 
analysed the humoral immune response of dog against Leishmania infantum 
parasite. The antigenic reaction of L. infantum polypeptides with sera 
from 31 dogs with parasitologically confirmed leishmaniosis was studied 
by using the immunoblot technique. Electrophoretic profile of the 
parasite extract showed more than 50 polypeptides, with molecular 
weights ranging from 12 to 170kDa. Among these polypeptides, 37 antigen 
components, ranging from 14 to 91kDa, were recognised by antibodies of L
. infantum infected dogs. Three polypeptides (14, 16 and 76kDa) reacted 
with all of the 31 serum samples. The other most frequently recognised 
antigens were those of 29.5, 32, 46, 59 and 66kDa with a sensitivity of 
87.1%, 93.6%, 96.8%, 87.1% and 80.6%, respectively. The 14 and 16kDa 
bands were the most intense and remained detectable until a serum 
dilution of 1:6400. No reaction of these two major antigens was observed
 with sera collected from 50 Leishmania-free dogs, living in the 
leishmaniosis-free region of Rabat in Morocco, whereas the crude antigen
 used in IFAT or ELISA lead to three false positive results. Four 
antigen components of 29, 41, 55, and 70kDa were recognised by some sera
 samples from negative controls. These results demonstrated the 
potential interest of the fractions of 14 and 16kDa in immunodiagnosis 
of canine leishmaniosis.




PMID: 16253120
 

TITLE: Interleukin-2-Activated Natural Killer Cells May Have a Direct Role in
the Control of Leishmania (Leishmania) amazonensis Promastigote and Macrophage
Infection.

AUTHORS: F C S Aranha, U Ribeiro, P Basse, C E P Corbett, M D Laurenti

AFFILIATION: Infectious Diseases Laboratory (LIM-50), Department of Pathology,
University of São Paulo Medical School, São Paulo, Brazil.

REFERENCE: Scand J Immunol 2005 Oct 62(4):334-41

To study the role of Natural Killer (NK) cells in Leishmania infection, 
peritoneal macrophages from BALB/c mice were infected with Leishmania (
Leishmania) amazonensis promastigotes and incubated with interleukin-2 (
IL-2)-activated NK (A-NK) cells at different ratios of A-NK cells to 
infected macrophages (5:1, 1:1, 0.2:1). The A-NK cells were added either
 together with the parasites (0-h group) or 24 h later (24-h group). 
Morphological studies of the cultures revealed predominance of parasitic
 debris within macrophages that were in close contact with A-NK cells 
and the decrease in parasite recovery was directly proportional to the A
-NK cell concentration used. Interferon-gamma (IFN-gamma) and IL-12 were
 detected in the supernatant at levels proportional to the A-NK cell 
concentration used. No significant difference was observed between the 
groups with respect to NO levels in the culture supernatant. When A-NK 
cells were added directly to the L. (L.) amazonensis promastigote 
cultures, the parasite recovery decreased proportional to the number of 
A-NK cells added. In vivo studies demonstrated smaller lesion sizes in 
animals inoculated with both parasites and A-NK cells compared with 
parasites alone. Histopathology of the skin lesions from animals 
receiving A-NK cells together with the parasites showed moderate 
parasitism and a nodular inflammatory infiltrate formed by mononuclear 
cells and a few vacuolized macrophages. In contrast, animals inoculated 
only with the parasites showed a highly parasitized dermis with 
infiltration of intensely vacuolized macrophages. These results 
demonstrate the role of A-NK cells in parasite lysis and in resistance 
of macrophages to L. (L.) amazonensis in the early phase of infection.




PMID: 16188725
 

TITLE: Designing and testing of an effective oil-in-water microemulsion drug
delivery system for in vivo application.

AUTHORS: S Gupta, S P Moulik, S Lala, M K Basu, S K Sanyal, S Datta

AFFILIATION: Centre for Surface Science, Department of Chemistry, Jadavpur
University, Kolkata, India. cssju at yahoo.co.uk

REFERENCE: Drug Deliv 2005 Sep-Oct 12(5):267-73

The phase behavior of a new psedoternary system of clove oil/Tween 20 
has been studied. Several compositions from the single-phase region were
 selected and their stability toward time, temperature, and electrolytes
 has been examined. A particular composition(clove oil/Tween 20/water as
 5/30/65) was chosen as the drug delivery system from the clear oil-in-
water zone of the pseudoternary system. The droplet dimension and the 
polydispersity state of the particular composition was determined by 
dynamic light scattering. A bioactive compound quarcetin was 
encapsulated in the vehicle. The efficacy of the drug in the vehicle was
 examined against leishmaniasis in hamster models. The hepatotoxicity of
 the vehicle (o/w microemulsion) with and without the drug quarcetin was
 examined by estimating serum alkaline phosphatase, glutamate pyruvate 
transaminase, urea, and creatinine.




REQUEST: [ sand fly ]

(2 articles match this request. 2 articles matching other requests removed)



REQUEST: [ sandfly ]

(1 article matches this request. 1 article matching other requests removed)














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