[leish-l] Fwd: Articles found by RefScout 09/02/2005 5/2005 part 1

[jeffreyj at usp.br]

    Date: Wed, 9 Feb 2005 12:01:20
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This is RefScout-Newsletter 5/2005 






Due to more than 100 requests your newsletter has been split. This is part 1.




REQUEST: [ leishmaniasis ]

(151 articles match this request. 31 articles matching other requests removed)







PMID: 15652330
 

TITLE: Activity of a paromomycin hydrophilic formulation for topical treatment
of infections by Leishmania (Leishmania) amazonensis and Leishmania (Viannia)
braziliensis.

AFFILIATION: Department of Clinical and Toxicological Analysis, Faculty of
Pharmacy, Federal University of Minas Gerais (UFMG), Av Antônio Carlos, 6627,
CEP 31270-901, Belo Horizonte, Minas Gerais, Brazil.

REFERENCE: Acta Trop 2005 Feb 93(2):161-7

Studies on in vitro skin permeation and in vivo anti-leishmanial 
activity in mice experimentally infected with Leishmania (Leishmania) 
major pointed out to the potential of a new paromomycin (PA) formulation
 (hydrophilic gel) for treatment of cutaneous leishmaniasis (CL). In 
this study, the activity of this formulation was evaluated in animals 
experimentally infected by Leishmania species that prevail in the New 
World. PA gel activity was compared to antimony treatment, since it is 
still the first choice treatment to the different clinical forms of 
leishmaniasis. The topical treatment activity with 10% PA gel in BALB/c 
mice infected by Leishmania (Leishmania) amazonensis was higher than 
that observed for parenteral antimony treatment, while the efficacy of 
these two regimes in hamsters infected by Leishmania (Viannia) 
braziliensis was similar. These results suggest that this formulation 
could be suitable for clinical studies and may represent an alternative 
novel formulation for topical treatment of CL.




PMID: 15652328
 

TITLE: Eco-epidemiological survey of Leishmania (Viannia) braziliensis American
cutaneous and mucocutaneous leishmaniasis in Ribeira Valley River, Parana
State, Brazil.

AFFILIATION: Universidade Federal do Paraná, Setor de Ciências Biológicas,
Departamento de Patologia Básica, Centro Politécnico, Jardim das Américas,
81.531-990, Curitiba, Paraná, Brazil.

REFERENCE: Acta Trop 2005 Feb 93(2):141-9

Leishmaniasis is endemic since last century in Adrianopolis Municipality
, Ribeira Valley and is a serious public health. A study carried out 
during 1993-2003 on epidemiological surveys conducted in rural 
communities showed 339 new cases of cutaneous leishmaniasis (CL) 
detected from four municipalities (Adrianopolis, Cerro Azul, Doutor 
Ulysses and Rio Branco do Sul). A larger prevalence of cutaneous lesions
 was observed in rural workers (36%), women with domestic activities (18
%), and younger students (31%). Multiple lesions were noticed in 53% of 
patients, but only one case of mucocutaneous leishmaniasis was reported
. Twenty stocks were isolated from patients with characteristics lesions
 and were identified as Leishmania (Viannia) braziliensis using multi-
locus enzyme electrophoresis (MLEE) and Random Amplified DNA (RAPD). In 
Phlebotominae survey, five species were obtained. Lutzomyia intermedia 
sl. represented 97.5% in peridomiciliar area and 100% in domicile. A 
canine serological survey made (Indirect Immunofluorescence Antibody 
Test, IFAT and Enzyme Linked Immunosorbent Assay, ELISA) in six rural 
county of Adrianopolis Municipality during 1998-1999 showed that 15.1% (
24/159) of dogs were sera reactive. No lesions were observed in dogs and
 no parasite was isolated from lymph node aspirates and biopsies. In 
wild reservoirs study, only seven animals (Cricetidae, Desmodus sp. and 
edentates) were captured, but no parasites were found in culture from 
deep organs. The paper presents results of our 10 years study on 
cutaneous leishmaniasis survey in the Ribeira River Valley, East Region 
of Parana State, Brazil. Environment changes in this region are also 
discussed.




PMID: 15633999
 

TITLE: In vitro and in vivo anti-leishmanial activity of triterpenoid saponins
isolated from Maesa balansae and some chemical derivatives.

AFFILIATION: Tibotec nv, Generaal De Wittelaan 11 bus 4, B-2800 Mechelen,
Belgium.

REFERENCE: J Med Chem 2005 Jan 48(1):32-7

The methanolic extract from the leaves of the Vietnamese medicinal plant
 Maesa balansae showed potent in vitro and in vivo activity against the 
tropical protozoal parasite Leishmania infantum. Bioassay-guided 
purification of the extract led to the identification of six 
triterpenoid saponins, maesabalides I-VI (1-6), each having a strong and
 specific anti-leishmanial activity. Maesabalide III (3) and IV (4) were
 the most potent with IC(50) values against intracellular amastigotes of
 about 7 and 14 ng/mL. In comparison, the IC(50) value of sodium 
stibogluconate, the reference drug for treatment of leishmaniasis, is 
only 5.6 microg/mL. No cytotoxicity was present on a human fibroblast (
MRC-5) cell line (CC(50) > 32 microg/mL). In vivo evaluation in the BALB
/C mouse model demonstrated that >90% reduction of liver amastigote 
burdens was obtained 1 week after a single subcutaneous dose at 0.2-0.4 
mg/kg was administered. Several chemical derivatives of maesabalides I-
VI were prepared in order to study the structure-activity relationship.




PMID: 15655736
 

TITLE: Differential interferon- gamma production characterizes the cytokine
responses to Leishmania and Mycobacterium leprae antigens in concomitant
mucocutaneous leishmaniasis and lepromatous leprosy.

AFFILIATION: Departamento de Imunologia, Instituto Oswaldo Cruz, Rio de Janeiro,
Brazil.

REFERENCE: Clin Infect Dis 2005 Jan 40(2):e5-12

BACKGROUND: Tegumentary leishmaniasis and leprosy display similar 
spectra of disease phenotypes, which are dependent on cell-mediated 
immunity to specific antigens. Diffuse cutaneous leishmaniasis and 
lepromatous leprosy represent the anergic end of the spectrum, whereas 
mucocutaneous leishmaniasis and tuberculoid leprosy are associated with 
marked antigen-specific cellular immune response. METHODS: We 
characterized and compared the cell-mediated response to Leishmania and 
Mycobacterium leprae antigens in a patient with an intriguing 
association of mucocutaneous leishmaniasis with lepromatous leprosy, 
which are at opposite ends of the immunopathological spectra of these 
diseases. This was done by performance of skin tests and by assessment 
of the cell proliferation and cytokine production of peripheral blood 
mononuclear cells (PBMCs). RESULTS: Strong skin-test reactions and PBMC 
proliferation were observed in response to Leishmania antigens but not 
to M. leprae antigens. The stimulation of PBMCs with Leishmania and M. 
leprae antigens induced comparable levels of tumor necrosis factor- 
alpha , interleukin-5, and interleukin-10. However, the interferon- 
gamma response to Leishmania antigens was remarkably high, and that to M
. leprae antigens was almost nil. CONCLUSIONS: We found that concomitant
 leprosy and tegumentary leishmaniasis can produce opposite polar forms 
associated, respectively, with absent or exaggerated cell-mediated 
immune responses to each pathogen. This suggests that independent 
mechanisms influence the clinical outcome of each infection. Moreover, 
interferon- gamma appears to play a major role in the clinical 
expression of these intracellular infections.




PMID: 15655163
 

TITLE: An unusual presentation of cutaneous leishmaniasis.

REFERENCE: Arch Dermatol 2005 Jan 141(1):109-10




PMID: 15589797
 

TITLE: Antibody response in patients with cutaneous leishmaniasis infected by
Leishmania (Viannia) braziliensis or Leishmania (Viannia) guyanensis in
Brazil.

AFFILIATION: Núcleo de Medicina Tropical, Faculdade de Medicina, Universidade
de Brasília, Caixa Postal 04517, Campus Universitário, Asa Norte, Brasília,
Distrito Federal 70919-970, Brazil.

REFERENCE: Acta Trop 2005 Jan 93(1):49-56

The antibody response against Leishmania (Leishmania) amazonensis crude 
antigen was measured through the indirect immunofluorescent assay (IFA) 
and the immunoenzymatic assay (ELISA) in 114 patients with cutaneous 
leishmaniasis (CL) in Brazil. Fifty-four patients were infected by 
Leishmania (Viannia) braziliensis, and 60 patients had L. (V.) 
guyanensis infection. Patients were comparable by age, sex, disease 
duration and the Montenegro skin test diameter. L. (V.) braziliensis-
infected patients showed significant lower number of ulcerated lesions, 
greater ulcerated area and higher proportion of lymph node enlargement. 
Sensitivity of IFA was 79.6% (95% CI 66.1-88.9) and 71.7% (95% CI 58.4-
82.2) for L. (V.) braziliensis and L. (V.) guyanensis-infected patients
, respectively (P=0.324). Sensitivity of ELISA was 98.2% (95% CI 88.8-99
.9) and 85.0% (95% CI 72.9-92.5) for L. (V.) braziliensis and L. (V.) 
guyanensis-infected patients, respectively (P=0.018). Significant 
differences were observed in the magnitude of the antibody response 
before treatment with higher levels detected in L. (V.) braziliensis-
infected patients by both serologic techniques. Eighty-four patients had
 serologic evaluations before and 12 weeks after treatment with 
meglumine antimoniate, 20mg/kg/day for 20 days. Significant lower optic 
density values were observed after treatment with both species 
independent of cure or failure. Our data showed that L. (V.) 
braziliensis induces a higher antibody response against L. (L.) 
amazonensis antigens than L. (V.) guyanensis and that down-modulation of
 the antibody response occurs shortly during disease evolution after 
treatment. Moreover the data support the use of ELISA as a better tool 
for detection of antibodies in CL.




PMID: 15603841
 

TITLE: Human and canine leishmaniasis in asymptomatic and symptomatic population
in Northwestern Greece.

AFFILIATION: Zoonoses and Parasitology Unit, Department of Microbiology, Medical
School, Dourouti University Campus, University of Ioannina, 45110 Ioannina,
Greece.

REFERENCE: J Infect 2005 Jan 50(1):53-60

The occurrence of human and canine Mediterranean visceral leishmaniasis
 (MVL) in Northwestern Greece was investigated during an 8-year survey (
1994-2001). A total of 1200 blood sera samples, collected from 
asymptomatic human population, and 1200 blood sera samples from 
asymptomatic dogs were screened for Leishmania infantum antibodies using
 the indirect immunofluorescence test (IFA). Also during the survey 111 
human subjects and 350 canines were referred as clinically suspect cases
 for MVL. Significant differences [Formula: see text] were found between
 the prevalence of MVL in symptomatic and asymptomatic human populations
 (12.6 and 0.5%, respectively), but a more modest difference was 
observed between symptomatic and asymptomatic canines (45.4 and 24.4%, 
respectively). From the results, it appears that Greece has a high 
background of canine leishmaniasis, which is likely to be a risk factor 
for the emergence of human MVL.




PMID: 15620480
 

TITLE: Pulcherrimasaponin, from the leaves of Calliandra pulcherrima, as
adjuvant for immunization in the murine model of visceral leishmaniasis.

AFFILIATION: Laboratório de Química de Plantas Medicinais, Núcleo de
Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, P.O.
Box 68045, CEP 21944-970 Rio de Janeiro, Brazil.

REFERENCE: Vaccine 2005 Jan 23(8):1061-71

A novel triterpenoidal saponin, called pulcherrimasaponin (CP05), 
isolated from the leaves of Calliandra pulcherrima Benth. shows 
remarkable similarities to the previously described potent adjuvant, 
QS21 saponin (Quillaja saponaria Molina). On the basis of chemical and 
physicochemical evidence, its structure was established as [3beta,
16alpha,28[2E,6S[2E,6S(2E,6S)]]]-olean-12-en-28-oic acid 3-[[O-alpha-l-
arabinopyranosyl-(1-->2)-O-alpha-l-arabinopyranosyl-(1-->6)-2-(
acetylamino)-2-deoxy-beta-d-glucopyranosyl]oxy]-16-hydroxy-O-beta-d-
glucopyranosyl-(1-->3)-O-[O-beta-d-xylopyranosyl-(1-->3)-beta-d-
xylopyranosyl-(1-->4)-O-6-deoxy-alpha-l-mannopyranosyl-(1-->2)-6-O-[6-[[
2-O-2,6-dimethyl-1-oxo-6-(beta-d-xylopyranosyloxy)-2,7-octadienyl]-[(6-
deoxy-beta-d-glucopyranosyl)oxy]-2,6-dimethyl-1-oxo-2,7-octadienyl]-beta
-d-xylopyranosyl]oxy]-2,6-dimethyl-1-oxo-2,7-octadienyl]-beta-d-
glucopyranosyl ester. In vivo toxicity assays disclosed similar and 
transitory local swelling and loss of hair but no lethality for mice. 
The haemolytic index was higher for QS21 (5mug/ml) than for CP05 (13mug/
ml). Mouse vaccination with either CP05 or QS21 in combination with the 
fucose-mannose ligand (FML) antigen of Leishmania donovani showed anti-
FML responses, significantly enhanced over the saponin and saline 
controls, in IgM, IgG, IgG1, IgG2a, IgG2b and IgG3. Antibody levels were
 similar for both vaccines in most subtypes. However, QS21-FML vaccine 
showed a 1.5 to 2.1 proportional increase over the CP05-FML vaccine in 
IgG, IgG2a and IgG3 responses. The delayed type of hypersensitivity 
against leishmanial antigen was impressively increased for CP05-FML and 
for QS21-FML-treated animals over controls (p<0.005). Enhancement was
 similar for both vaccines (p<0.05). The safety analysis and the 
effect on humoral and cellular immune responses demonstrated that the 
novel Calliandra pulcherrima Benth. CP05 saponin is a potential 
candidate for a vaccine adjuvant.




PMID: 15620471
 

TITLE: Protective immunogenicity of the paraflagellar rod protein 2 of
Leishmania mexicana.

AFFILIATION: Centro Internacional de Entrenamiento e Investigaciones Médicas
(CIDEIM), Apartado Aéreo 5390, Cali, Colombia.

REFERENCE: Vaccine 2005 Jan 23(8):984-95

Paraflagellar rod proteins (PFR) are a potent immunogen against 
experimental Trypanosoma cruzi infection. PFR are highly conserved among
 kinetoplastid parasites. We therefore evaluated the immunogenicity of 
the Leishmania mexicana pfr-2 gene and protein product in the hamster 
model of American cutaneous leishmaniasis. Immunization with pfr-2 DNA-
induced specific antibody, confirming immunogenicity. Subsequent 
challenge with 10,000 and 500 stationary phase L. mexicana promastigotes
 respectively, resulted in delayed appearance of lesions, and 
significant reduction in lesions post infection in male hamsters, yet 
exacerbated lesions in female hamsters. Immunization with recombinant 
PFR-2 protein (rPFR-2) prevented lesion development in female hamsters 
challenged with L. panamensis, but was ineffective against L. mexicana. 
Nevertheless, prime boost immunization of female hamsters with rPFR and 
pfr-2 DNA significantly reduced lesion size following challenge with 500
 L. mexicana promastigotes, supporting the relevance of PFR-2 as a 
potential vaccine constituent.




PMID: 15649196
 

TITLE: A randomized, double-blind, placebo-controlled clinical trial of
itraconazole in the treatment of cutaneous leishmaniasis.

AFFILIATION: Center for Research & Training in Skin Diseases & Leprosy, Tehran
University of Medical Sciences, Tehran, Iran.

REFERENCE: J Eur Acad Dermatol Venereol 2005 Jan 19(1):80-3

ABSTRACT Background Several modalities have been used for the treatment 
of cutaneous leishmaniasis (CL) with various results. In vitro and in 
vivo studies have shown inhibitory effects of azole drugs on Leishmania 
parasites. Objectives To evaluate the efficacy and tolerability of oral 
itraconazole in the treatment of CL caused by L. major. Methods A total 
of 200 patients with parasitologically confirmed CL with a duration of 
less than 45 days from a well known L. major endemic area were included 
in a randomized, double-blind, placebo-controlled clinical trial. The 
patients received either itraconazole 200 mg daily (100 patients) or 
placebo (100 patients) for 8 weeks. The primary outcome measures were 
clinical cure (complete re-epithelization of all lesions) and 
parasitological cure at the end of the treatment. Results Eighty-three 
patients in the itraconazole and 75 patients in the placebo group 
completed the treatment course. After 8 weeks of treatment, clinical 
cure was observed in 59% and 53% and parasitological cure was observed 
in 83% and 76% of patients in the itraconazole and placebo groups, 
respectively, which were not significantly different. There was no 
difference in the rate of adverse events. Conclusions An 8-week course 
of oral itraconazole was not more effective than placebo in the 
treatment of CL.




PMID: 15620822
 

TITLE: Treatment of paediatric visceral leishmaniasis: amphotericin B or
pentavalent antimony compounds?

AFFILIATION: Second Department of Pediatrics, University of Athens, P. & A.
Kyriakou Children's Hospital, Athens 11527, Greece.

REFERENCE: Int J Antimicrob Agents 2005 Jan 25(1):26-30

Pentavalent antimony compounds and amphotericin B lipid formulations 
have been found highly active for the treatment of visceral 
leishmaniasis. This study focuses on which treatment is preferable in 
the best interests of the child. Records were reviewed of children in 
our hospital aged 0-14 years, diagnosed with visceral leishmaniasis, 
during the last 4 years. Twenty-nine children were identified. Ten were 
treated with meglumine antimonate (20mg/kg/day for 21 days) and remained
 in hospital for 11-28 days (median 19 days), while 19 patients received
 liposomal amphotericin B at four different dosage schemes and were in 
hospital for 6-11 days (median 7 days). All of the patients were cured 
regardless of the treatment regime they followed. No relapses were noted
. Liposomal amphotericin B would be preferable to meglumine antimonate 
if the reduction in hospital stay and hence the convenience of the 
patient balance the cost of medication. The optimal duration of 
treatment with liposomal amphotericin B remains to be determined.




PMID: 15644104
 

TITLE: Therapy of ocular and visceral leishmaniasis in a cat.

AFFILIATION: Veterinary Teaching Hospital, Facultat de Veterinà ria, Universitat
Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

REFERENCE: Vet Ophthalmol 2005 Jan-Feb 8(1):71-5

An 8-year-old, spayed female Domestic Short-haired cat was referred for 
further evaluation of chronic lymphocytic-plasmacytic stomatitis and 
bilateral ocular disease. The cat had been treated with systemic 
glucocorticoids for several months. Initial ophthalmic examination 
revealed bilateral deep stromal corneal ulcers, exudative panuveitis and
 secondary glaucoma. Mature mild neutrophilia and monocytosis were 
detected on complete blood cell count. Abnormalities in the serum 
profile were hyperglycemia, mild azotemia, hyperglobulinemia and 
moderate polyclonal gammapathy. Urinalysis revealed glucosuria without 
ketonuria. Diabetes mellitus was diagnosed and treatment with long-
acting insulin was started. An enzyme-linked immunosorbent assay was 
highly positive for leishmaniasis, and treatment with allopurinol was 
started. Although specific topical treatment was applied, melting ulcers
 progressed to corneal perforation and both eyes were enucleated. Ocular
 histology showed large numbers of intracellular organisms compatible 
with amastigotes of the genus Leishmania located in the uveal tract, 
cornea, sclera and retina. Results of inmunohistochemistry staining on 
ocular samples were positive for Leishmania. Bone marrow cytology 
demonstrated numerous macrophages with intracytoplasmatic Leishmania. 
Polymerase chain reaction results on bone marrow for Leishmania were 
positive. Three weeks later, hypoglycemic episodes permitted withdrawal 
of the insulin therapy. To the authors' knowledge this is the first case
 of ocular and visceral leishmaniasis diagnosed in vivo and under 
systemic treatment in a cat.




PMID: 15644865
 

TITLE: Antimony-induced cardiomyopathy in guinea-pig and protection by
L-carnitine.

AFFILIATION: 1CNRS UMR 6542, Physiologie des Cellules Cardiaques et Vasculaires,
Faculté des Sciences, Parc de Grandmont, 37200 Tours, France.

REFERENCE: Br J Pharmacol 2005 Jan 144(1):17-27

Antimony (Sb) is the mainstay for the treatment of Leishmaniasis. It has
 serious, often lethal, cardiovascular side effects. The objective of 
this study was to examine the effects of Sb treatment upon the 
electrocardiogram (ECG), myocyte contractility (assessed by monitoring 
sarcomere length during field stimulation), whole-cell action potential
 (AP) and calcium current (I(Ca)) of the guinea-pig and to evaluate L-
carnitine as a cardioprotective agent.Guinea-pigs received daily 
injections of either saline, Sb(V), Sb(III), L-carnitine or L-carnitine 
with Sb(III). Eight lead ECGs were recorded under halothane anaesthesia 
every 4 days. At the end of each treatment regime, animals were killed 
and ventricular myocytes were enzymatically isolated.Treatment with Sb(V
) for 26 days prolonged the QT interval of the ECG. Treatment with Sb(
III) was lethal within 2 days for approximately 50% of the animals. The 
survivors showed ECG alterations similar to those described in man: T 
wave flattening and/or inversion, depression of the ST segment, and 
elongation of RR and QT intervals. Their ventricular myocytes showed 
impaired contraction responses to changes in stimulus frequency, 
elongated AP and reduced I(Ca).Combined treatment with L-carnitine and 
Sb(III) delayed mortality. Prior treatment with L-carnitine followed by 
combined treatment with L-carnitine and Sb(III) reduced mortality to &lt
;10% over 12 days and these animals showed normal ECG. Their myocytes 
showed normal contractility and AP.It is concluded that L-carnitine has 
a preventive cardioprotective role against antimony-induced 
cardiomyopathy. The mechanism of action of L-carnitine may be to counter
 oxidative stress caused by Sb(III).British Journal of Pharmacology (
2005) 144, 17-27. doi:10.1038/sj.bjp.0706030.




PMID: 15567136
 

TITLE: Sudanese mucosal leishmaniasis: isolation of a parasite within the
Leishmania donovani complex that differs genotypically from L. donovani causing
classical visceral leishmaniasis.

AFFILIATION: Institute of Endemic Diseases, University of Khartoum, P.O. Box
102, Khartoum, Sudan.

REFERENCE: Infect Genet Evol 2005 Jan 5(1):29-33

Mucosal leishmaniasis, which is a sporadic disease in the Sudan, was 
shown by isoenzyme characterization and PCR to be caused by Leishmania 
donovani. However, it was not clear if the parasite was exactly the same
 strain as that causing visceral leishmaniasis (VL), or of a different 
strain. We utilized a new generation of molecular DNA markers, 
minisatellites and kinetoplast DNA, for rapid characterization of the 
parasite. The results show that the genotypes of some of the parasites 
causing VL are different from those causing mucosal leishmaniasis. The L
. donovani isolates causing visceral disease, as well as post-kala-azar 
mucosal leishmaniasis (PKML), have been shown to possess characteristic 
haplotypes. However, sequencing of a portion of the cytochrome oxidase 
II (COII) gene indicates that the parasite that invades the oral mucosa 
is divergent from other parasites causing VL. It appears to possess 
features of a more ancestral parasite with pronounced sequence homology 
to L. major. This agrees with earlier studies where isolates of mucosal 
leishmaniasis have been shown to possess an isoenzyme profile distinct 
from L. donovani and a different geographical distribution, albeit often
 overlapping with that of L. donovani.




PMID: 15340016
 

TITLE: Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking.

AFFILIATION: Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth
Drive, Cleveland, OH 44109-1998. Email: eficker at metrohealth.org.

REFERENCE: J Pharmacol Exp Ther 2005 Jan 312(1):316-23

The diamidine pentamidine is used to treat leishmaniasis, 
trypanosomiasis, and Pneumocystis carinii pneumonia. Treatment may be 
accompanied by prolongation of the QT interval of the electrocardiogram 
and torsades de pointes tachycardias. Up to now, it has been thought 
that therapeutic compounds causing QT prolongation are associated with 
direct block of the cardiac potassium channel human ether a-go-go-
related gene (hERG), which encodes the alpha subunit of cardiac I(Kr) 
currents. We show that pentamidine has no acute effects on currents 
produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents
 and the guinea pig cardiac action potential were also not affected. 
After overnight exposure, however, pentamidine reduced hERG currents and
 inhibited trafficking and maturation of hERG with IC(50) values of 5 to
 8 muM similar to therapeutic concentrations. Surface expression 
determined in a chemiluminescence assay was reduced on exposure to 10, 
30, and 100 muM pentamidine by about 30, 40, and 70%, respectively. 
These effects were specific for hERG since expression of hKv1.5, KvLQT1/
minK, and Kv4.3 was not altered. In isolated guinea pig ventricular 
myocytes, 10 muM pentamidine prolonged action potential duration APD(90
) from 374.3 +/- 57.1 to 893.9 +/- 86.2 ms on overnight incubation. I(Kr
) tail current density was reduced from 0.61 +/- 0.09 to 0.39 +/- 0.04 
pA/pF. We conclude that pentamidine prolongs the cardiac action 
potential by block of hERG trafficking and reduction of the number of 
functional hERG channels at the cell surface. We propose that 
pentamidine, like arsenic trioxide, produces QT prolongation and 
torsades de pointes in patients by inhibition of hERG trafficking.




PMID: 15629362
 

TITLE: Isolation of integral membrane proteins of Leishmania promastigotes and
evaluation of their prophylactic potential in hamsters against experimental
visceral leishmaniasis.

AFFILIATION: Division of Parasitology, Central Drug Research Institute, Lucknow
226001, India.

REFERENCE: Vaccine 2005 Jan 23(9):1189-96

The integral membrane proteins (IMP's) of promastigotes of two virulent 
strain of Leishmania (L.) donovani Dd8 and Leishmania (L.) infantum LV9 
and one avirulent viscerotropic strain Leishmania tropica UR6 were 
extracted by phase separation technique using a non-ionic detergent &
quot;Triton X-114". This detergent is homogeneous at 0 degrees C 
but divides in an aqueous phase and a detergent phase at above 20 
degrees C. The phase partition resulted in solubilisation of hydrophilic
 proteins in aqueous phase, and IMP's with an amphiphilic nature were 
recovered in the detergent phase. The strain wise quantitative recovery 
rates of IMP's were estimated. These proteins were purified by chill 
methanol centrifugation and used as vaccinogen, alone or in combination 
with adjuvant against L. donovani challenge in hamster model. Among all 
the combinations, hamsters immunised with IMP of L. donovani (Dd8) in 
combination with CFA resulted in 75% parasite inhibition in spleen (P &
lt; 0.001), however, 61.14% (P < 0.001) and 77.60% (P < 0.001) 
parasitic inhibition was achieved in liver and bone marrow respectively 
as compared to their unvaccinated counter part. Similar combinations 
with UR6 and LV9 strain inhibited the parasite establishment up to 65.12
% (P < 0.001) and 66.87% (P < 0.001), respectively on splenic site
. The specific IgG level against (Dd8 strain) soluble leishmania 
promastigote antigen was monitored at different stages by enzyme linked 
immunosorbent assay (ELISA) corresponds to the level of parasitic 
establishment. Similar observations were made in cases of LV9 and UR6 
strains. However, significant lymphoproliferative response to IMPs of 
Dd8 strain (SI 3.5-4.9, P < 0.001) was noticed in all IMP + CFA 
vaccinated animals. Thus, this study will provide a lead for more 
manipulative trials to develop a subunit vaccine against the fatal 
disease.




PMID: 15589796
 

TITLE: Positive Montenegro skin test among patients with sporotrichosis in Rio
De Janeiro.

AFFILIATION: Instituto de Pesquisa Clínica Evandro Chagas (IPEC), Fundação
Oswaldo Cruz (Fiocruz), Av. Brasil 4365, Manguinhos, Rio de Janeiro CEP
21045-900, Brazil.

REFERENCE: Acta Trop 2005 Jan 93(1):41-7

We studied 52 patients with sporotrichosis confirmed by isolation of 
Sporothrix schenckii and reactivity to the Montenegro skin test (MST) 
during an ongoing outbreak of this mycosis in Rio de Janeiro. The 
objective was to emphasize the importance of parasitological 
confirmation and the possibility of incorrect diagnosis based on the 
lesion's appearance, epidemiological information, and immunological 
tests. The antigen used for the MST was conserved in either thimerosal 1
:10,000 (group 1) or 0.4% phenol (group 2). Nineteen patients (39%) in 
group 1 and seven (12%) in group 2 presented an induration>/=10mm (p<
0.001). Sera from three patients (6.7%) reacted to indirect 
immunofluorescence (IIF) for leishmaniasis, while sera from 10 patients
 (22.2%) reacted to enzyme-linked immunosorbent assay (ELISA). Fifteen 
patients (28.8%) presented up to two lesions, with a predominance of 
ulcers. Forty-four patients (84.6%) were treated with itraconazole. In 
the differential diagnosis between sporotrichosis and cutaneous 
leishmaniasis, the possibility of co-infection, allergy to the reagent 
diluent, and cross-reactions should be further investigated, especially 
in regions with limited laboratory facilities.




PMID: 15619517
 

TITLE: Interleukin-12 augments a Th1-type immune response manifested as
lymphocyte proliferation and interferon gamma production in Leishmania
infantum-infected dogs.

AFFILIATION: School of Veterinary Medicine, Hebrew University of Jerusalem, P.O.
Box 12, Rehovot 76100, Israel; The Kuvin Center for the Study of Tropical and
Infectious Diseases, Hebrew University-Hadassah Medical School, Jerusalem,
Israel.

REFERENCE: Int J Parasitol 2005 Jan 35(1):63-73

The dog is the major reservoir for human visceral leishmaniasis caused 
by Leishmania infantum. Interleukin-12 is considered to have an 
essential role in the development of both innate and adaptive immunity 
to Leishmania spp. and other intracellular pathogens. This study focused
 on the influence of IL-12 in experimental and natural canine visceral 
leishmaniasis. Responses of peripheral blood mononuclear cells to IL-12
, interleukin-10 and Leishmania soluble antigen were evaluated in L. 
infantum experimentally infected oligosymptomatic beagles, uninfected 
beagles, naturally infected polysymptomatic dogs, and their matched 
uninfected controls. Leishmania soluble antigen induced strong 
peripheral blood mononuclear cells proliferation both in experimentally 
infected dogs (median stimulation index [SI]=15.01), and in naturally 
infected dogs (SI=8.86), but not by cells from the control groups. IL-12
 addition further enhanced cell proliferation in naturally (SI=14.95), 
but not in experimentally infected animals. Peripheral blood mononuclear
 cells from experimentally infected dogs were able to produce 
significant amounts of IFN-gamma (3.39ng/ml) upon LSA stimulation, but 
no such production was detected in cells from naturally infected or 
control animals. Interestingly, addition of IL-12 reversed the 
inhibitory effect of LSA on IFN-gamma production by cells from 
polysymptomatic naturally infected dogs and the uninfected beagles (4.84
 and 7.45ng/ml, respectively), and further increased IFN-gamma 
production by peripheral blood mononuclear cells from experimentally 
infected oligosymptomatic dogs (29.28ng/ml). IFN-gamma mRNA expression 
correlated well with IFN-gamma production. Addition of IL-10 to 
Leishmania soluble antigen stimulated peripheral blood mononuclear cells
 inhibited proliferation and IFN-gamma production in experimentally 
infected dogs. Thus, the ability of IL-12 to augment IFN-gamma 
production by peripheral blood mononuclear cells from dogs with 
experimental or natural symptomatic canine visceral leishmaniasis makes 
it a good candidate for cytokine therapy in dogs that are refractory to 
current therapy.




PMID: 15626462
 

TITLE: Semi-quantitative analysis of cytokine expression in asymptomatic canine
leishmaniasis.

AFFILIATION: WHO Collaborating Centre for Leishmaniasis, Parasitology Service,
National Centre of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.

REFERENCE: Vet Immunol Immunopathol 2005 Jan 103(1-2):67-75

The dog is the main reservoir of Leishmania infantum, the parasite 
responsible for visceral leishmaniasis in Mediterranean countries. The 
infection in dogs shows different clinical presentations, from 
subclinical/asymptomatic to a fully developed disease, depending on the 
host's immune responses. The Th1/Th2 dichotomy is not clear in the 
different forms of canine leishmaniasis, since the data available from 
studies of immunity response in canine leishmaniasis are scarce and 
fragmented. The present work describes the cytokine expression in 
peripheral blood mononuclear cells (PBMC) obtained from asymptomatic 
dogs experimentally infected with L. infantum that present a cellular 
protective immune response. The results obtained from freshly isolated 
PBMC showed expressions of TNF-alpha, IL-2, IFN-gamma, IL-10 and IL-18 
mRNA, similar to those from non-infected dogs. However, there was almost
 no expression of IL-4 mRNA detected in the asymptomatic infected dogs 
compared to the control dogs. Unspecific stimulation with ConA promoted 
the expression in a greater or lower degree of all the cytokines studied
. In vitro stimulation of PBMC with soluble leishmanial antigen (SLA) 
promoted the expression of IL-2, IFN-gamma, TNF-alpha, IL-18, IL-4, IL-6
 and IL-10 mRNA, with the two first being specifically induced. Although
 both Th1 and Th2 cytokines are produced, cell mediated immunity 
observed in these L. infantum-infected asymptomatic dogs depended on the
 preferential expression of Th1 cytokines.




PMID: 15606511
 

TITLE: Comparative study of cutaneous leishmaniasis in human immunodeficiency
virus (HIV)-infected patients and non-HIV-infected patients in French Guiana.

AFFILIATION: Institut Guyanais de Dermatologie Tropicale, Service de
Dermatologie, Centre Hospitalier de Cayenne, Rue des Flamboyants, BP 6006,
97300 Cayenne, French Guiana.

REFERENCE: Br J Dermatol 2004 Dec 151(6):1165-71

Summary Background Few data are available on cutaneous leishmaniasis 
caused by dermotropic species in human immunodeficiency virus (HIV)-
infected patients. Objectives To describe nine cases of cutaneous 
leishmaniasis in HIV+ patients and to compare their clinical features 
and their response to treatment with those of HIV- patients with the 
forms of leishmaniasis commonly found in French Guiana. Methods A case-
control study was carried out between July 1994 and December 2000 in 
French Guiana. We compared the following variables in nine HIV-infected 
patients with leishmaniasis and 27 matched controls: clinical type of 
leishmaniasis, number of lesions, presence of lymphangitis and 
adenopathy, the rate of recovery after treatment, and recurrence or 
reinfection. Results Eight of the HIV-infected patients had localized 
cutaneous leishmaniasis and one had mucocutaneous leishmaniasis. All of 
the controls had localized cutaneous leishmaniasis. Leishmania 
guyanensis was the only species isolated from HIV-infected subjects. HIV
-Leishmania coinfected patients had a higher rate of recurrence or 
reinfection (P < 0.02) and a lower rate of recovery after one 
treatment cycle with pentamidine (P < 0.02) than did HIV- subjects. 
The CD4+ lymphocyte counts exceeded 200 mm(-3) in all HIV+ patients at 
the time of the diagnosis with leishmaniasis. Conclusions In French 
Guiana, cutaneous leishmaniasis in moderately immunosuppressed HIV-
infected subjects (> 200 CD4+ T cells mm(-3)) is characterized by a 
higher rate of recurrence or reinfection and is more difficult to treat 
than that in HIV- subjects.




PMID: 15579454
 

TITLE: Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the
control of Leishmania donovani infection.

AFFILIATION: Immunology and Infection Laboratory and Australian Centre for
International and Tropical Health and Nutrition, Queensland Institute of
Medical Research, Herston, Queensland, Australia 4029. chrise at qimr.edu.au

REFERENCE: Am J Pathol 2004 Dec 165(6):2123-33

Tumor necrosis factor (TNF) is critical for the control of visceral 
leishmaniasis caused by Leishmania donovani. However, the role of the 
related cytokine lymphotoxin (LT) alpha in this infection is unknown. 
Here we report that C57BL/6 mice deficient in TNF (B6.TNF(-/-)) or LT 
alpha (B6.LT alpha(-/-)) have increased susceptibility to hepatic L. 
donovani infection. Furthermore, the outcome of infection in bone marrow
 chimeric mice is dependent on donor hematopoietic cells, indicating 
that developmental defects in lymphoid organs were not responsible for 
increased susceptibility to L. donovani. Although both LT alpha and TNF 
regulated the migration of leukocytes into the sinusoidal area of the 
infected liver, their roles were distinct. LT alpha was essential for 
migration of leukocytes from periportal areas, an event consistent with 
LT alpha-dependent up-regulation of VCAM-1 on liver sinusoid lining 
cells, whereas TNF was essential for leukocyte recruitment to the liver
. During visceral leishmaniasis, both cytokines were produced by radio-
resistant cells and by CD4(+) T cells. LT alpha and TNF production by 
the former was required for granuloma assembly, while production of 
these cytokines by CD4(+) T cells was necessary to control parasite 
growth. The production of inducible nitric oxide synthase was also found
 to be deficient in TNF- and LT alpha-deficient infected mice. These 
results demonstrate that both LT alpha and TNF are required for control 
of L. donovani infection in noncompensatory ways.




PMID: 15599651
 

TITLE: Evaluation of a latex agglutination test (KAtex) for detection of
Leishmania antigen in urine of patients with HIV-Leishmania coinfection: value
in diagnosis and post-treatment follow-up.

AFFILIATION: Laboratori de Parasitologia, Facultat de Farmà cia, Universitat de
Barcelona, Avenida Joan XXIII s/n, 08028, Barcelona, Spain, mcriera at ub.edu.

REFERENCE: Eur J Clin Microbiol Infect Dis 2004 Dec 23(12):899-904

The usefulness of antigen detection in urine as an alternative tool for 
diagnosis of leishmaniasis and post-treatment follow-up in patients with
 Leishmania-HIV coinfection was evaluated with a latex agglutination 
test (KAtex; Kalon Biological, UK). Forty-nine HIV-infected patients 
with visceral leishmaniasis were included in the study. Antigen 
detection in urine (ADU) was positive in 42 of 49 (sensitivity, 85.7%) 
samples obtained during a primary episode. After treatment, a follow-up 
study in 23 patients was performed by simultaneous ADU and culture of 
peripheral blood mononuclear cells in 148 determinations. The two 
methods gave concordant results in 94 cases, 38 of which were positive 
and 56 negative. In five cases, ADU was negative and culture of 
peripheral blood mononuclear cells was positive: two of these cases 
corresponded to clinical relapses. In 49 cases, culture of peripheral 
blood mononuclear cells was negative and ADU was positive. In the 
absence of clinical symptoms, the detection of parasite antigens in 71 
of 130 (54.6%) urine samples was not associated with clinical disease. 
The Kaplan-Meier estimates of the probability of relapse at 6, 12, 18, 
and 24 months were 16% (95%CI, 15-17%), 20% (95%CI, 18-22%), 31% (95%CI
, 27-35%), and 71% (95%CI, 52-89%), respectively, in patients with a 
positive ADU result. In contrast, when ADU was negative, the probability
 of relapse was 5% at 6 months (95%CI, 2-8%) (only 2 of 11 patients who 
relapsed had a negative test). ADU by KAtex is appropriate for primary 
diagnosis of visceral leishmaniasis, for monitoring the efficacy of 
treatment, and for detection of subclinical infection.




PMID: 15614453
 

TITLE: Challenges and new discoveries in the treatment of leishmaniasis.

AFFILIATION: Division of Clinical Microbiology, All India Institute of Medical
Sciences, P.O. Box 4938, New Delhi, India, ssingh56 at hotmail.com.

REFERENCE: J Infect Chemother 2004 Dec 10(6):307-15

Leishmaniasis is a parasitic disease caused by a hemoflagellate, 
Leishmania spp. The parasite is transmitted by the bite of an infected 
female phlebotomine sandfly. The disease is prevalent throughout the 
world and in at least 88 countries. Human leishmanial infections may 
manifest in any of the four most common forms. Depending on the 
causative species, it can manifest as cutaneous leishmaniasis (CL), 
mucocutaneous leishmaniasis (MCL), diffused cutaneous leishmaniasis (DCL
), or visceral leishmaniasis (VL). Although there are nearly 25 
compounds having antileishmanial effects, only a few are used for humans
 and most of these are parenteral. The oldest was urea stibamine, 
developed in India in 1922. The original drug had severe toxic effects, 
and later on its pentavalent compounds were prepared, which remained the
 sole treatment modality for several decades and saved millions of lives
. However, reports of unresponsiveness to pentavalent sodium antimony 
gluconate (SAG) started in the 1970s, and in some parts of India about a
 quarter of kala-azar cases are reported to have developed resistance 
even to its higher doses. This development led to successful clinical 
trials of pentamidine and amphotericine B. The latter, an antifungal 
compound, was also found to be highly nephrotoxic, and to minimize these
 side effects various colloidal and lipid formulations have been 
prepared. These preparations are comparatively safe but are exorbitantly
 costly. In the past two decades, more focus has been given to finding 
oral drugs to minimize injection-associated complications, including 
blood-borne infection. Various drugs were reported effective, including 
antifungal ketoconazole. However, the most promising drug found is an 
anticancer compound, miltefosine, that belongs to the 
alkylphosphocholine group. The drug has undergone experimental and 
clinical trials and found to be 94%-97% effective. However, the drug 
cannot be given during pregnancy and shows severe gastrointestinal side 
effects. Moreover, its cost will be another limiting factor. Other drugs
 such as paromomycin, allopurinol, and sitamaquine have been reported 
with variable cure rates. Because of these limitations, a combination 
therapy, preferably coupled with specific parasite enzyme inhibitors, is
 the only hope.




PMID: 15610512
 

TITLE: Anti-desmoglein-1 antibodies in onchocerciasis, leishmaniasis and chagas
disease suggest a possible etiological link to fogo selvagem.

AFFILIATION: Department of Dermatology, University of North Carolina at Chapel
Hill, North Carolina, USA;

REFERENCE: J Invest Dermatol 2004 Dec 123(6):1045-51

Pemphigus foliaceus (PF) and the endemic form Fogo Selvagem (FS) are 
mediated by pathogenic antibodies to the EC1-2 domains of desmoglein-1. 
There is a preclinical phase with antibodies to only EC5. Based on 
geographic clustering of cases, FS is thought to have an, as yet 
unidentified, environmental trigger. In this study we have searched for 
anti-desmoglein-1 antibodies in sera from parasitic (leishmaniasis, 
Chagas, and onchocerciasis), and infectious diseases (leprosy and South 
American (SA) blastomycosis), which are prevalent in the same geographic
 regions of Brazil as FS. A specific and sensitive desmoglein-1 ELISA 
detected antibodies in 34 of 41 onchocerciasis (83%), 38 of 88 
leishmaniasis (43%), 18 of 31 Chagas disease (58%), 7 of 28 SA 
blastomycosis (25%), and 14 of 83 leprosy sera (17%). These sera 
recognized epitopes restricted to the EC5 domain. These findings 
identify several etiological factors for FS. It is hypothesized that a 
component of insect vector saliva, rather than the parasite itself may 
trigger an antibody response to EC-5. In persons with the known HLA 
susceptibility alleles and living in endemic areas, a response to the 
EC1-2 domains may subsequently develop by epitope spreading with 
associated clinical signs of FS.








PMID: 15588096
 

TITLE: Identification of novel parasitic cysteine protease inhibitors using
virtual screening. 1. The ChemBridge database.

AFFILIATION: Department of Medicinal Chemistry, School of Pharmacy, University
of Mississippi, University, Mississippi 38677-1848, USA.

REFERENCE: J Med Chem 2004 Dec 47(26):6609-15

Trypanosomiasis, leishmaniasis, and malaria are major parasitic diseases
 in developing countries. The existing chemotherapy of these diseases 
suffers from lack of safe and effective drugs and/or the presence of 
widespread drug resistance. Cysteine proteases are exciting novel 
targets for antiparasitic drug design. Virtual screening was performed 
in an attempt to identify novel druglike nonpeptide inhibitors of 
parasitic cysteine proteases. The ChemBridge database consisting of 
approximately 241 000 compounds was screened against homology models of 
falcipain-2 and falcipain-3 in three consecutive stages of docking. A 
total of 24 diverse inhibitors were identified from an initial group of 
84, of which 12 compounds appeared to be dual inhibitors of falcipain-2 
and falcipain-3. Four compounds showed inhibition of both the malarial 
cysteine proteases as well as Leishmania donovani cysteine protease.




PMID: 15598262
 

TITLE: Infection rates with Leishmania donovani and Mycobacterium tuberculosis
in a village in eastern Sudan.

AFFILIATION: Faculty of Medicine, Khartoum University, Khartoum, Sudan.

REFERENCE: Trop Med Int Health 2004 Dec 9(12):1305-11

Summary Background Leishmania-tuberculosis co-infection is not uncommon 
in clinical practice in East Africa, but little is known about the 
epidemiology of this problem at population level. A cross-sectional 
household survey was carried out in an active visceral leishmaniasis (VL
) focus in Eastern Sudan in February 2002. Methods All inhabitants of 
Marbata village in Atbara River Area, Gedarif State, who gave informed 
consent, underwent both a leishmanin skin test (LST) and a tuberculin 
test for infection with L. donovani and Mycobacterium tuberculosis. All 
subjects were clinically screened for VL and tuberculosis (TB). Results 
About 66% (252 of 382) were LST-positive, 26% (100 of 382) were 
tuberculin-positive and 20% (77 of 382) were positive for both tests. By
 the age of 15, more than 60% of inhabitants were LST-positive, but <
20% were tuberculin-positive. By the age of 30, these percentages 
increased to 100 and 50%. No association was found at the individual 
level between leishmanial and tuberculous infection after controlling 
for age. Conclusion In this community study, we found no association 
between the risk of infection with L. donovani and M. tuberculosis. 
However, the progression to active VL disease might be different in M. 
tuberculosis-infected than in non-infected persons and vice versa. 
Prospective studies are needed to document the prognosis of TB/VL co-
infection.




PMID: 15516924
 

TITLE: Deletion of a conserved Il4 silencer impairs T helper type 1-mediated
immunity.

AFFILIATION: Department of Pathology, Harvard Medical School, Boston,
Massachusetts 02115, USA.

REFERENCE: Nat Immunol 2004 Dec 5(12):1251-9

Helper T cell differentiation involves silencing as well as activation 
of gene expression. We have identified a conserved silencer of the gene 
encoding interleukin 4 (Il4) marked by DNase I hypersensitivity (HS IV) 
and permissive chromatin structure in all helper T cells. Deletion of HS
 IV increased Il4 and Il13 transcription by naive T cells and led to T 
helper type 2 skewing in vitro. HS IV controlled Il4 silencing during T 
helper type 1 differentiation, as HS IV-deficient T helper type 1 cells 
that expressed interferon-gamma also produced abundant interleukin 4 in 
vitro and in vivo. Despite mounting a vigorous interferon-gamma response
, HS IV-deficient mice were more susceptible to Leishmania major 
infection than were wild-type littermate control mice, showing a 
critical function for Il4 silencing in T helper type 1-mediated immunity.




PMID: 15567123
 

TITLE: Human genetics of intracellular infectious diseases: molecular and
cellular immunity against mycobacteria and salmonellae.

AFFILIATION: Department of Infectious Diseases, Leiden University Medical
Centre, Leiden, Netherlands.

REFERENCE: Lancet Infect Dis 2004 Dec 4(12):739-49

The ability to develop adequate immunity to intracellular bacterial 
pathogens is unequally distributed among human beings. In the case of 
tuberculosis, for example, infection with Mycobacterium tuberculosis 
results in disease in 5-10% of exposed individuals, whereas the 
remainder control infection effectively. Similar interindividual 
differences in disease susceptibility are characteristic features of 
leprosy, typhoid fever, leishmaniasis, and other chronic infectious 
diseases, including viral infections. The outcome of infection is 
influenced by many factors, such as nutritional status, co-infections, 
exposure to environmental microbes, and previous vaccinations. It is 
clear, however, that genetic host factors also play an important part in
 controlling disease susceptibility to intracellular pathogens. Recently
, patients with severe infections due to otherwise poorly pathogenic 
mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis BCG) 
or Salmonella spp have been identified. Many of these patients were 
unable to produce or respond to interferon gamma, due to deleterious 
mutations in genes that encode major proteins in the type 1 cytokine (
interleukin 12/interleukin 23/interferon gamma) axis (interleukin 12p40/
interleukin 23p40, IL12 receptor beta1/IL23 receptor beta1, interferon 
gamma receptors 1 and 2, or signal transducer and activator of 
transcription 1). This axis is a major immunoregulatory system that 
bridges innate and adaptive immunity. Unusual mycobacterial infections 
were also reported in several patients with genetic defects in inhibitor
 of NFkappaB kinase gamma, a key regulatory molecule in the nuclear 
factor kappaB pathway. New findings discussed in this review provide 
further and sometimes surprising insights into the role of type 1 
cytokines, and into the unexpected heterogeneity seen in these syndromes.




PMID: 15569809
 

TITLE: New world mucosal and cutaneous leishmaniasis: an emerging health problem
among British travellers.

AFFILIATION: Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT.
stevelawn at yahoo.co.uk

REFERENCE: QJM 2004 Dec 97(12):781-8

BACKGROUND: Mucosal leishmaniasis (ML) is an important complication of 
new world cutaneous leishmaniasis (CL) caused by species of the 
Leishmania Viannia subgenus. Previous reports of ML among travellers to 
Latin America are few. AIMS: To determine the annual number of cases of 
CL due to L. Viannia species diagnosed at this institution and to 
correlate this with changing patterns of travel. Secondly, to document 
the clinical presentation, diagnosis, treatment and outcome of ML at 
this institution. DESIGN: Retrospective observational study. METHODS: 
Data were collected from a clinical database, laboratory records, 
patient case notes and an international passenger survey. RESULTS: 
Between 1995 and 2003, the annual number of cases of CL (total 79) 
steadily increased from 4 per year to 18 per year; the estimated number 
of travellers from the UK to Latin America increased 3.5-fold. Six cases
 of ML were diagnosed among British travellers in 1995 (1), 1997 (1) and
 2002 (4). These infections were acquired in Bolivia (3), Colombia (2) 
and Belize (1). Nasopharyngeal symptoms developed 0-15 months after 
returning to the UK. Four patients had concurrent CL at diagnosis. 
Diagnosis of ML was delayed up to 6 months from the onset of symptoms. 
Mucosal biopsies from all 6 patients were PCR-positive for L. (Viannia) 
DNA; microscopy and culture were less sensitive. ML relapsed in one 
patient following treatment. DISCUSSION: Increasing travel to Latin 
America from the UK was associated with an increasing number of 
diagnoses of L. Viannia CL. ML is likely to emerge as a more frequently 
imported infection among such travellers. Familiarity with these 
diseases is important for prompt diagnosis and optimal management.




PMID: 15596127
 

TITLE: Dendritic cells in Leishmania infection.

AFFILIATION: Department of Internal Medicine, Immunology and Infectious
Diseases, University of Bari Medical School, Bari, Italy.

REFERENCE: Microbes Infect 2004 Dec 6(15):1402-9

Dendritic cells (DCs) are key elements of the immune system, which 
function as sentinel in the periphery and alert T lymphocytes about the 
type of invading antigen and address their polarisation, in order to 
mount an efficacious immune response. Leishmania spp. are parasitic 
protozoa which may cause severe disease in humans and domestic animals. 
In this work, the main studies concerning the role of DCs in Leishmania 
infection are reviewed, in both the murine and human models. In 
particular, the importance of the genetic status of the hosts and of the
 different Leishmania species in modulating DC-mediated immune response 
is examined. In addition, different approaches of DC-based vaccination 
against experimental leishmaniasis, which could have important future 
applications, are summarised.




PMID: 15578370
 

TITLE: Old world leishmaniasis: an emerging infection among deployed US military
and civilian workers.

AFFILIATION: Leishmania Diagnostics Laboratory, Walter Reed Army Institute of
Research, Silver Spring, MD, USA.

REFERENCE: Clin Infect Dis 2004 Dec 39(11):1674-80

Many veterans of Operation Iraqi Freedom are now returning to the United
 States after potential exposure to leishmaniasis. In the past year, 
large numbers of leishmaniasis cases of a magnitude not encountered in 
the United States since World War II have challenged clinicians in both 
the military and the civilian sectors. Many Reserve and National Guard 
troops were deployed to Iraq and are now back in their communities. 
Hundreds of leishmaniasis cases, which were managed by a few 
practitioners initially, permitted further appreciation of the 
epidemiology and diagnostic and treatment options for Old World 
leishmaniasis. We describe the current situation, with on-the-ground 
experience, complimented by a literature review, and we provide a 
practical list of options for the clinician likely to encounter this 
parasitic infection in the coming months and years.




PMID: 15490237
 

TITLE: Distribution of sandfly species in relation to canine leishmaniasis from
the Ebro Valley to Valencia, northeastern Spain.

AFFILIATION: Molecular Systematics Laboratory, Entomology Department, Natural
History Museum, Cromwell Road, SW7 5BD, London, UK.

REFERENCE: Parasitol Res 2004 Dec 94(6):416-20

In Spain, only two of the 12 recorded species of sandflies, Phlebotomus
 (Larroussius) ariasi Tonnoir and P. (L.) perniciosus Newstead, are 
proven vectors of Leishmania infantum Nicolle, the causative agent of 
endemic leishmaniasis. Studies of the distributions of phlebotomine 
sandflies are important for evaluating the possible effects of climate 
warming on any northward or altitudinal range shifts of leishmaniasis or
 the other diseases they transmit. We describe a recent sandfly survey 
in Spain, starting in the northern Ebro Valley and continuing southeast 
into the Levante region of the Mediterranean coast. Sandflies ( P. 
ariasi only) were found for the first time in the northern province of 
Alava, in the upper Ebro Valley, where cases of canine leishmaniasis 
have been described during the last decade. Throughout the provinces 
sampled, P. ariasi predominated over P. perniciosus in cooler 
bioclimatic zones, and this statistically significant pattern was more 
marked than that with higher altitudes.




PMID: 15355995
 

TITLE: Camptothecin-induced Imbalance in Intracellular Cation Homeostasis
Regulates Programmed Cell Death in Unicellular Hemoflagellate Leishmania
donovani.

AFFILIATION: Division of Molecular Parasitology, Division of Infectious Disease,
and Division of Immunology, Indian Institute of Chemical Biology, 4, Raja S.C.
Mullick Road, Kolkata 700 032, India.

REFERENCE: J Biol Chem 2004 Dec 279(50):52366-75

Leishmania, a unicellular trypanosomatid protozoan parasite, causes a 
wide range of human diseases ranging from the localized self-healing 
cutaneous lesions to fatal visceral leishmaniasis. However, it undergoes
 a process of programmed cell death during treatment with the 
topoisomerase I poison camptothecin (CPT). The present study shows that 
CPT-induced formation of reactive oxygen species increases the level of 
cytosolic calcium through the release of calcium ions from intracellular
 stores as well as by influx of extracellular calcium. Elevation of 
cytosolic calcium is responsible for depolarization of mitochondrial 
membrane potential (DeltaPsi(m)), which is followed by a significant 
decrease in intracellular pH levels. CPT-induced oxidative stress also 
causes impairment of the Na(+)-K(+)-ATPase pump and subsequently 
decreases the intracellular K(+) level in leishmanial cells. A decrease 
in both intracellular pH and K(+) levels propagates the apoptotic 
process through activation of caspase 3-like proteases by rapid 
formation of cytochrome c-mediated apoptotic complex. In addition to 
caspase-like protease activation, a lower level of intracellular K(+) 
also enhances the activation of apoptotic nucleases at the late stage of
 apoptosis. This suggests that the physiological level of pH and K(+) 
are inhibitory for apoptotic DNA fragmentation and caspase-like protease
 activation in leishmanial cells. Moreover, unlike mammalian cells, the 
intracellular ATP level gradually decreases with an increase in the 
number of apoptotic cells after the loss of DeltaPsi(m). Taken together
, the elucidation of biochemical events, which tightly regulate the 
process of growth arrest and death of Leishmania donovani promastigotes
, allows us to define a more comprehensive view of cell death during 
treatment with CPT.




PMID: 15582528
 

TITLE: Natural killer cells and innate immunity to protozoan pathogens.

AFFILIATION: Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

REFERENCE: Int J Parasitol 2004 Dec 34(13-14):1517-28

Natural killer (NK) cells are lymphoid cells that mediate significant 
cytotoxic activity and produce high levels of pro-inflammatory cytokines
 in response to infection. During viral infection, NK cell cytotoxicity 
and cytokine production is induced principally by monocyte-macrophage- 
and dendritic cell-derived cytokines but virally encoded ligands for NK 
cells are also beginning to be described. NK derived interferon-gamma (
IFN-gamma) production is also essential for control of several protozoal
 infections including toxoplasmosis, trypanosomiasis, leishmaniasis and 
malaria. The activation of NK cells by protozoan pathogens is also 
believed to be cytokine-mediated although some recent studies suggest 
that direct recognition of parasites by NK cells also occurs. Both 
indirect signalling via accessory cell-derived cytokines and direct 
signalling, presumably through NK receptors, are needed in order for 
human malaria parasites (Plasmodium falciparum) to optimally stimulate 
NK activity.




PMID: 15587314
 

TITLE: Identification of cutaneous leishmaniasis in Egypt by hybridization of
PCR amplified mini-exon repeats.

AFFILIATION: Department of Medical Parasitology, Faculty of medicine, Suez Canal
University, Ismailia, Egypt.

REFERENCE: J Egypt Soc Parasitol 2004 Dec 34(3):881-92

Polymerase Chain Reaction (PCR) had been used to amplify the mini-exon 
gene repeat from 30 clinically and parasitologically positively cases of
 zoonotic cutaneous leishmaniasis. It revealed that they possess 440-460
 bp mini-exon gene that belongs to Old world Leishmania. Hybridization 
of the PCR-amplified mini-exon repeats was performed. A single pair of 
PCR primers within a conserved region of the mini-exon repeat was used 
to amplify the repeats of the 30 cases. Oligonucleotide hybridization 
probes for the detection and identification of the PCR-amplified repeats
 were constructed from alignment of mini-exon intron and intergenic 
sequences. The probes of Leishmania major and Leishmania tropic, which 
are supposed to be present in the research area, were used to identify 
the causative species. They revealed that the all collected samples are 
belonging to L. major.




PMID: 15621973
 

TITLE: Another Hazard of War: Infectious Diseases: Leishmaniasis, malaria
threaten troops, millions worldwide.

AFFILIATION: Barbara A. Goldrick is a consultant and certified nurse
epidemiologist in Chatham, MA, and coordinates Emerging Infections:
bagoldrick at comcast.net.

REFERENCE: Am J Nurs 2004 Dec 104(12):64-6




PMID: 15557613
 

TITLE: The Leishmania major LACK antigen with an immunodominant epitope at amino
acids 156 to 173 is not required for early Th2 development in BALB/c mice.

AFFILIATION: Departmrnt of Medicine, Howard Hughes Medical Institute, University
of California-San Francisco, UCSF Medical Center, Room C-443, 521 Parnassus
Avenue, San Francisco, CA 94143-0654, USA.

REFERENCE: Infect Immun 2004 Dec 72(12):6924-31

The Leishmania major LACK antigen contains an immunodominant epitope at 
amino acids 156 to 173 (LACK(156-173)) that is believed to nucleate the 
pathological Th2 immune response in susceptible BALB/c mice. To test 
this hypothesis, we generated L. major parasites that express a mutated 
LACK that fails to activate Vbeta4/Valpha8 T-cell receptor transgenic T 
cells specific for this epitope. Although mutant parasites attenuated 
the expansion of endogenous LACK-specific, interleukin-4 (IL-4)-
expressing, CD4 T cells compared to wild-type parasites in vivo, the 
overall frequency of IL-4 and gamma interferon-secreting lymphocytes was
 similar to that elicited by wild-type L. major. Mutant parasites 
demonstrated diminished amastigote viability and delayed lesion 
development in mice, although parasites could be recovered over 200 days
 after infection. Complementation with a wild-type lack fusion construct
 partially rescued these defects, indicating a role for endogenous LACK 
in parasitism. Mice inoculated with mutant parasites were not protected 
against subsequent infection with wild-type L. major.




PMID: 15642973
 

TITLE: Treatment of visceral leishmaniasis in 2004.

AFFILIATION: Department of Medicine, Weill Medical College of Cornell
University, New York, New York.

REFERENCE: Am J Trop Med Hyg 2004 Dec 71(6):787-94

In 2004, visceral leishmaniasis (kala-azar) maintains its status as a 
neglected, if not "most neglected" disease. Lack of affordable
 new drugs, still a basic unsolved problem, has also been joined by 
additional therapeutic obstacles including large-scale resistance to 
pentavalent antimony (Sb) in India and coinfection with human immuno-
deficiency virus in all endemic regions. Nevertheless, available 
treatment options have actually expanded because the energetic clinical 
trials effort of the past decade has yielded tangible advances. This 
progress includes successful application of less expensive generic Sb; 
rediscovery of the high-level efficacy of amphotericin B; implementation
 of short-course parenteral regimens (lipid formulations of amphotericin
 B); potential to replace Sb and amphotericin B with price-capped 
paromyomycin; and identification of the first effective oral agent (
miltefosine). How to sustain and move this progress ahead, make new 
advances practical (e.g., affordable, and therefore, deployable), and 
how to translate promising experimental approaches into actual therapy 
remain difficult next steps in the treatment of kala-azar.




PMID: 15642009
 

TITLE: Bionomics of phlebotomine sandflies in the Galilee focus of cutaneous
leishmaniasis in northern Israel.

AFFILIATION: Department of Parasitology, Kuvin Centre for the Study of
Infectious and Tropical Diseases, The Hebrew University -Hadassah Medical
School, Jerusalem, Israel.

REFERENCE: Med Vet Entomol 2004 Dec 18(4):418-28

Abstract. The bionomics of phlebotomine sandflies (Diptera: Psychodidae
) were studied for three years (2001-2003) in the Galilee focus of 
cutaneous leishmaniasis in northern Israel, where the causative 
Leishmania tropica (Kinetoplastida: Trypanosomatidae) is transmitted by 
Phlebotomus (Adlerius) arabicus Theodor and Phlebotomus (Paraphlebotomus
) sergenti Parrot, comprising 22% and 8%, respectively, of the local 
sandfly fauna sampled by light traps. The predominant species overall 
was Phlebotomus (Larroussius) tobbi Adler & Theodor (51%) with 
lesser numbers of Phlebotomus (Adlerius) simici Theodor (11%), 
Phlebotomus (Larroussius) syriacus Adler & Theodor (5%), Phlebotomus
 (Larroussius) perfiliewi Perfil'ev (3%) and Phlebotomus (Phlebotomus) 
papatasi Scopoli (0.05%). Sandfly adult populations were prevalent from 
April to November and peaked between June and August, being more 
abundant through the summer in irrigated habitats, such as gardens and 
orchards, than in open grassland. Of the two cutaneous leishmaniasis 
vectors, P. sergenti preferred boulder mounds located at the outskirts 
of settlements, whereas P. arabicus was more abundant overall and near 
houses in particular. Females of all these sandfly species displayed a 
peak of activity after sunset (20.00-22.00 hours), whereas activity of 
males persisted longer through the night. Another slight increase in 
activity was noted before dawn (02.00-04.00 hours). Phlebotomus arabicus
 appears to be the main vector of L. tropica in the Galilee focus, due 
to its denser populations, more endophily and preference for 
peridomestic habitats than shown by P. sergenti in northern Israel.




PMID: 15608773
 

TITLE: [Poor patients do not make a market]

AFFILIATION: Médecins Sans Frontières, Dadaab, North-Eastern Province, Kenya.
oeyhole at online.no

REFERENCE: Tidsskr Nor Laegeforen 2004 Dec 124(24):3226-8




PMID: 15648691
 

TITLE: Intake of nutrient supplements affects multiplication of Leishmania
donovani in hamsters.

AFFILIATION: Central Drug Research Institute, Lucknow - 226001, India.

REFERENCE: Parasitology 2004 Dec 129(Pt 6):685-91

The role of the essential nutrients, vitamins A, B (complex), C and E 
and iron, as prophylactic as well as supportive therapy in experimental 
visceral leishmaniasis (VL), was studied in hamsters. Prophylactic 
administration of vitamin C (50, 100 and 250 mg/kg) from day 15 to day 0
 (15 doses) significantly reduced the intake of Leishmania donovani in 
hamsters but had no therapeutic effect. In contrast, vitamins A, B 
complex and E and iron, whether used prophylactically or therapeutically
, promoted parasite multiplication. The efficacy of sodium 
stibogluconate, a reference antileishmanial drug, was appreciably 
improved in animals administered prophylactically with vitamin C. 
However, supplementation of vitamin C during established infections 
resulted in reduced drug action. The results show that the prophylactic 
use of vitamin C may prevent the onset of leishmania infection and 
cautions against the indiscriminate use of nutrient supplements such as 
vitamin A, B complex, and E and iron in VL endemic areas.




PMID: 15589169
 

TITLE: Stromal cells direct local differentiation of regulatory dendritic
cells.

AFFILIATION: Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

REFERENCE: Immunity 2004 Dec 21(6):805-16

CD11c(hi) dendritic cells (DC) play an essential role during the 
initiation of cell-mediated immunity. Recently, CD11c(lo)CD45RB(hi) DC 
with regulatory properties have been described. However, the origins of 
regulatory DC are poorly understood. Here, we show that spleen-derived 
stromal cells promote selective development of CD11c(lo)CD45RB(+) IL-10-
producing regulatory DC from lineage-negative c-kit(+) progenitor cells
. These DC have the capacity to suppress T cell responses and induce IL-
10-producing regulatory T cells in vitro and to induce antigen-specific 
tolerance in vivo. Furthermore, stromal cells from mice infected with 
Leishmania donovani more effectively supported differentiation of these 
highly potent regulatory DC. The ability of tissue stromal cells to 
direct the development of DC with a regulatory phenotype thus provides a
 new mechanism for local immune regulation.




PMID: 15569787
 

TITLE: Comparison of generic to branded pentavalent antimony for treatment of
new world cutaneous leishmaniasis.

AFFILIATION: Consorcio de Investigaciones Bioclínicas, Bogota, Colombia;
Fundación Fader, Bogota, Colombia; Hospital de Clinicas, La Paz, Bolivia;
North Bethesda, Maryland.

REFERENCE: Am J Trop Med Hyg 2004 Nov 71(5):577-81

The cost of generic pentavalent antimony (generic stibogluconate) is 
approximately one-sixth that of branded pentavalent antimony (
stibogluconate in the form of Pentostam((R)) or meglumine antimoniate in
 the form of Glucantime((R))). We compared generic stibogluconate to 
Pentostam and Glucantime for the treatment of cutaneous leishmaniasis 
patients in Bolivia and Colombia. For all 114 patients, the per-protocol
 cure rates were 83-91% and the intent-to-treat cure rates were 75-83%. 
The highest values were in the generic stibogluconate group. The 
incidence of pancreatic enzyme abnormalities was 48-88% and the 
incidence of liver enzyme abnormalities was 48-87%. The lowest 
incidences were in the generic stibogluconate group. The efficacy and 
tolerance of inexpensive generic stibogluconate appears comparable to 
branded formulations for the treatment of cutaneous leishmaniasis in 
these endemic regions.




PMID: 15546498
 

TITLE: Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis:
an ex vivo and in vitro study.

AFFILIATION: LIMI, Gonçalo Moniz Research Center -Oswaldo Cruz Foundation
(FIOCRUZ), Rua Waldemar Falcao 121, 40295-001 Salvador-BA, Brazil.
johan at cpqgm.fiocruz.br

REFERENCE: BMC Infect Dis 2004 Nov 4(1):50

BACKGROUND: The process of elimination of intracellular pathogens, such 
as Leishmania, requires a Th1 type immune response, whereas a dominant 
Th2 response leads to exacerbated disease. Experimental human zinc 
deficiency decreases Th1 but not Th2 immune response. We investigated if
 zinc and copper levels differ in different clinical forms of 
leishmaniasis, and if these trace metals might be involved in the immune
 response towards the parasite. METHODS: Blood was collected from 31 
patients with either localized cutaneous (LCL), mucosal (ML) or visceral
 (VL) leishmaniasis, as well as from 25 controls from endemic and non-
endemic areas. Anti-Leishmania humoral and cellular immune response were
 evaluated by quantifying specific plasma IgG, lymphoproliferation and 
cytokine production, respectively. Plasma levels of Cu and Zn were 
quantified by atomic absorption spectrophotometry. RESULTS: A 
significant decrease in plasma Zn was observed in all three patient 
groups (p < 0.01 for LCL and ML, p < 0.001 for VL), as compared to
 controls, but only VL (7/10) and ML (1/7) patients displayed overt Zn 
deficiency. Plasma Cu was increased in LCL and VL (p < 0.001) but not
 in ML, and was strongly correlated to anti-Leishmania IgG (Spearman r
 = 0.65, p = 0.0028). Cu/Zn ratios were highest in patients with 
deficient cellular (VL<<LCL<ML) and exacerbated humoral (VL>LCL
>ML) immune response. Ex vivo production of parasite-induced IFN-gamma 
was negatively correlated to plasma Cu levels in LCL (r = -0.57, p = 0.
01). In vitro, increased Cu levels inhibited IFN-gamma production. 
CONCLUSIONS: 1. Zn deficiency in VL and ML indicate possible therapeutic
 administration of Zn in these severe forms of leishmaniasis. 2. Plasma 
Cu positively correlates to humoral immune response across patient 
groups. 3. Environmentally or genetically determined increases in Cu 
levels might augment susceptibility to infection with intracellular 
pathogens, by causing a decrease in IFN-gamma production.




PMID: 15605963
 

TITLE: What is your diagnosis? Cutaneous leishmaniasis.

AFFILIATION: Department of Family Practice, Spangdahlem Airbase, Germany.

REFERENCE: Cutis 2004 Nov 74(5):284, 287-8




PMID: 15604485
 

TITLE: Seroprevalence of Leishmania infantum in Northwestern Spain, an Area
Traditionally Considered Free of Leishmaniasis.

AFFILIATION: Departamento de Medicina y Cirugía Animal, Facultad de
Veterinaria, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n.
28040, Madrid, Spain. angelehr at vet.ucm.es.

REFERENCE: Ann N Y Acad Sci 2004 Nov 1026():154-7

Northwestern Spain has traditionally been considered to be free from 
leishmaniasis. The aim of this work was to determine the prevalence of 
canine leishmaniasis in this area and to assess the influence of several
 risk factors on the incidence of this disease. A total of 479 dogs 
attended at different veterinary clinics in northwestern Spain were 
tested for L. infantum with the immunofluorescent antibody (IFA) test. 
The seroprevalence of L. infantum in this area was 3.7%. Most of the 
seropositive dogs lived in two locations: Valdcorras (seroprevalence of 
29.2%) and Ourense (seroprevalence of 7.5%). The detection of high 
antibody titers in most of the seropositive dogs (many of which 
presented clinical signs) coupled with the certainity that some of these
 dogs had never been outside their home areas indicates the presence of 
this zoonosis in these two sites. On the other hand, companion dogs were
 significantly less likely to acquire the disease than sheep dogs, 
hunting dogs, and those from kennels.




PMID: 15604504
 

TITLE: The immunology of leishmania infection and the implications for vaccine
development.

AFFILIATION: Department of Veterinary Pathology, College of Veterinary Medicine,
Iowa State University, Ames, Iowa 50011. jonesdou at iastate.edu.

REFERENCE: Ann N Y Acad Sci 2004 Nov 1026():267-72

Leishmania parasites are vector-borne protozoal pathogens found in 
tropical and subtropical regions of both the Old and New World. These 
parasites can cause visceral or cutaneous disease, and the pathology of 
the infection is determined by both host immune factors and species/
strain differences of the parasite. Dogs are an important reservoir for 
maintaining the population of Leishmania parasites that can lead to 
visceral leishmaniasis in humans, and a vaccination approach may be an 
effective method for reducing the numbers of infected dogs. Resistance 
to leishmaniasis has been consistently associated with a T helper 1 
immune response, characterized by the production of IFN-gamma by the 
antigen-specific lymphocyte population. The development of this Th1 
response has been shown to be dependent upon both cytokines and 
dendritic cells during T cell activation. However, the development of a 
Leishmania vaccine effective in preventing these chronic diseases has 
proven to be a challenge. Vaccine trials have focused on whole-killed or
 subunit vaccines with adjuvants. Newer experimental strategies involve 
the attenuation of the Leishmania parasite via gene deletion 
technologies or the expression of specific Leishmania peptides within 
attenuated organisms, such as Bacillus Calmette Guerin. DNA vaccines and
 dendritic cell potentiators, such as CpG oligodeoxynucleotides and Flt-
3 ligand, are also in the early stage of development. In addition, as 
part of blocking the transmission cycle of leishmaniasis, several 
laboratories are also exploring the possibility of immunomodulating the 
host toward the bite of the sand fly.




PMID: 15569785
 

TITLE: Elevated plasma levels of interferon (IFN)-gamma, IFN-gamma inducing
cytokines, and IFN-gamma inducible CXC chemokines in visceral leishmaniasis.

AFFILIATION: Faculty of Medicine, Department of Microbiology, Immunology and
Parasitology, and Institute of Pathobiology, Addis Ababa University, PO Box
9086, Addis Ababa, Ethiopia. a_hailu at hotmail.com

REFERENCE: Am J Trop Med Hyg 2004 Nov 71(5):561-7

Interferon (IFN)- gamma plays an important role during immune responses 
against leishmaniasis. Production of IFN-gamma is regulated by 
interleukin (IL)-12, IL-18, and IL-15. Interferon-gamma-inducible 
protein (IP)-10 and monokine induced by IFN-gamma (Mig) are CXC 
chemokines, the production of which, at least in part, is IFN-gamma 
dependent. A follow-up study of individuals infected with Leishmania 
donovani was undertaken in an area of Ethiopia endemic for visceral 
leishmaniasis (VL). Plasma levels of IFN-gamma, IL-12p40, IL-18, IL-15, 
IP-10, and Mig were markedly elevated in symptomatic VL patients (n = 70
) compared with individuals with asymptomatic Leishmania infections (n
 = 39), malaria patients (n = 13), and healthy controls from the endemic
 area (n = 12). A significant decrease of IFN-gamma and all mediators 
was observed after treatment of VL patients (n = 33). These data show 
that increased plasma levels of IFN-gamma, as well as the mediators 
involved in the production and the activity of this cytokine, are 
characteristic of active VL in humans, and may play an important 
immunopathogenic role. The data also suggest that in patients with VL, 
the production of type 1 cytokines is not depressed, but there appears 
to be an unresponsiveness to the stimuli of type 1 cytokines. The 
underlying causes of immunologic unresponsiveness remain a subject of 
further investigation.




PMID: 15604481
 

TITLE: TaqMan-Based Detection of Leishmania infantum DNA Using Canine Samples.

AFFILIATION: Istituto Zooprofilattico Sperimentale of Sicily, Palermo, Italy.
sreale at pa.izs.it.

REFERENCE: Ann N Y Acad Sci 2004 Nov 1026():139-43

Leishmaniasis is a typical example of a worldwide diffused zoonosis. 
Geographic distribution depends on the presence of sand fly vectors and 
animal reservoirs. In Southern Europe, canines are considered the main 
reservoir of infection, and the phlebotomines are the vectors. In Sicily
, as in all Mediterranean areas, sand flies are present almost all year 
around because the climate permits an uninterrupted lifecycle for the 
vectors. Visceral leishmaniasis is becoming a real public health concern
 especially in endemic areas; in fact, it is an opportunistic infection 
in immunocompromised patients and in HIV-positive subjects. In Italy, 
the visceral form of the disease is due exclusively to Leishmania 
infantum ZMON1, and its prevalence is growing. We have developed a 
highly accurate, reproducible, and sensible real-time polymerase chain 
reaction (PCR) assay. In a procedure that used a specific couple of 
primers, a 117-bp fragment was amplified from minicircle kinetoplast DNA
 (kDNA). The assay was able to detect even a single parasite (200 fg of 
DNA). In fact, a single parasite contains hundreds of kinetoplast 
minicircles for each class. We applied a rapid extraction method coupled
 with the real-time PCR assay. It was not only as sensitive as a 
conventional PCR assay for detection of Leishmania kDNA, but also more 
rapid. The assay is useful for the diagnosis of leishmaniasis in dogs 
and humans, and it facilitates the monitoring of parasite levels during 
pharmacological treatment.








PMID: 15577769
 

TITLE: Cutaneous leishmaniasis in soldiers returning from deployment to Iraq.

AFFILIATION: Department of Dermatology, Reynolds Army Community Hospital, Fort
Sill, Oklahoma, USA. jpehoushek at cox.net

REFERENCE: J Am Acad Dermatol 2004 Nov 51(5 Suppl):S197-200

Cutaneous leishmaniasis is becoming a frequently encountered problem in 
soldiers returning from deployments to areas in Southwest Asia. Two 
cases of cutaneous leishmaniasis diagnosed at a military treatment 
facility in soldiers returning from Iraq are presented. Diagnostic 
considerations and procedures are reviewed as are the histopathologic 
findings and treatment options.




PMID: 15574294
 

TITLE: [Visceral leishmaniasis in a patient treated with chemotherapy and
radiotherapy for a cavum carcinoma.]

AFFILIATION: Departamento de Oncología.Clínica Universitaria de Navarra.
Universidad de Navarra. Pamplona. Navarra. España.

REFERENCE: Med Clin (Barc) 2004 Nov 123(19):759




PMID: 15482882
 

TITLE: Comparison of different tissue sampling for PCR-based diagnosis and
follow-up of canine visceral leishmaniosis.

AFFILIATION: Dipartimento di Scienze Cliniche Veterinarie, Università di Napoli
Federico II, Via F. Delpino 1, 80137 Naples, Italy.

REFERENCE: Vet Parasitol 2004 Nov 125(3-4):251-62

In this study, different types of tissue sampling for PCR-based 
diagnosis and follow-up of canine visceral leishmaniosis were compared. 
Skin, whole blood and lymph node samples were collected from 95 
naturally infected dogs living in South Italy, where the disease is 
endemic. Twenty-nine of these 95 dogs, treated with meglumine 
administered concurrently with allopurinol for 30 days, and then with 
allopurinol alone, were monitored during a period of 2 years. The DNA 
extracted from the clinical specimens was amplified by PCR using as 
target DNA a 116-bp fragment in the constant region of the kinetoplast 
DNA minicircle. PCR analysis was more sensitive than indirect 
immunofluorescence antibody test in detecting Leishmania infection in 
symptomatic dogs: 99% of lymph node samples resulted positive, whereas 
94% of blood samples and 95% of skin samples gave a positive result. PCR
 analysis of samples from dogs followed up 2 years showed that: (1) all 
subjects resulted positive in at least one of the three types of samples
; (2) all time the dogs had a relapse, PCR resulted positive in all 
three types of samples; (3) when dogs were apparently healthy, PCR 
analysis was positive on skin and lymph node samples, but not always on 
blood samples. Since lymph node sampling is invasive and sometimes 
difficult in healthy asymptomatic dogs, our results suggest that, 
independently from the presence or not of cutaneous lesions, skin biopsy
 represents a good substratum for PCR-based diagnosis and follow-up of 
canine visceral leishmaniosis.




PMID: 15569784
 

TITLE: Disseminated cutaneous leishmaniasis due to Leishmania guyanensis: case
of a patient with 425 lesions.

AFFILIATION: Institut Guyanais de Dermatologie Tropicale, Service de
Dermatologie et Service Hospitalo-Universitaire de Parasitologie-Mycologie,
Centre Hospitalier de Cayenne, Cayenne, French Guiana.

REFERENCE: Am J Trop Med Hyg 2004 Nov 71(5):558-60

Disseminated cutaneous leishmaniasis is characterized by the presence of
 a large (> or =10) number of lesions at several anatomic sites (head, 
limbs, and trunk). Most of the lesions are small, papular, and appear 
simultaneously with or secondarily to one or several ulcerated lesions 
of localized cutaneous leishmaniasis. We report the first case of 
disseminated cutaneous leishmaniasis in French Guiana. It concerns a 24-
year-old woman who tested negative for human immunodeficiency virus (HIV
). The disease began with three lesions that became ulcerated. One week 
later, multiple papulo-nodular lesions appeared. We counted a total of 
425 lesions. Leishmania were observed in the lesions. The species 
involved was L. guyanensis, which has never been described in a case of 
disseminated cutaneous leishmaniasis. The patient was rapidly cured by a
 single course of pentamidine. Disseminated cutaneous leishmaniasis 
should be distinguished from other types of leishmaniasis with multiple 
lesions. These include anergic diffuse cutaneous leishmaniasis, post-
kala-azar leishmaniasis, and leishmaniasis associated with HIV infection.




PMID: 15555069
 

TITLE: Spectrum of clinical disease in a series of 135 hospitalised HIV-infected
patients from north India.

AFFILIATION: Department of Medicine, All India Institute of Medical Sciences,
New Delhi, India. sksharma at aiims.ac.in.

REFERENCE: BMC Infect Dis 2004 Nov 4(1):52

BACKGROUND: Literature on the spectrum of opportunistic disease in human
 immunodeficiency virus (HIV)-infected patients from developing 
countries is sparse. The objective of this study was to document the 
spectrum and determine the frequency of various opportunistic infections
 (OIs) and non-infectious opportunistic diseases, in hospitalised HIV-
infected patients from north India. METHODS: One hundred and thirty five
 consecutive, HIV-infected patients (age 34 +/- 10 years, females 17%) 
admitted to a tertiary care hospital in north India, for the evaluation 
and management of an OI or HIV-related disorder between January 2000 and
 July 2003, were studied. RESULTS: Fever (71%) and weight loss (65%) 
were the commonest presenting symptoms. Heterosexual transmission was 
the commonest mode of HIV-acquisition. Tuberculosis (TB) was the 
commonest OI (71%) followed by candidiasis (39.3%), Pneumocystis 
jiroveci pneumonia (PCP) (7.4%), cryptococcal meningitis and cerebral 
toxoplasmosis (3.7% each). Most of the cases of TB were disseminated (64
%). Apart from other well-recognised OIs, two patients had visceral 
leishmaniasis. Two cases of HIV-associated lymphoma were encountered. 
CD4+ cell counts were done in 109 patients. Majority of the patients (82
.6%) had CD4+ counts <200 cells/muL. Fifty patients (46%) had CD4+ 
counts <50 cells/muL. Only 50 patients (37%) received antiretroviral 
therapy. Twenty one patients (16%) died during hospital stay. All but 
one deaths were due to TB (16 patients; 76%) and PCP (4 patients; 19%). 
CONCLUSIONS: A wide spectrum of disease, including both OIs and non-
infectious opportunistic diseases, is seen in hospitalised HIV-infected 
patients from north India. Tuberculosis remains the most common OI and 
is the commonest cause of death in these patients.




PMID: 15654419
 

TITLE: Epidemiology of leishmaniasis in Ecuador: current status of knowledge - A
review.

AFFILIATION: Department of Parasitology, Kochi Medical School, Kochi University,
Kochi, 783-8505, Japan.

REFERENCE: Mem Inst Oswaldo Cruz 2004 Nov 99(7):663-72

Although leishmaniasis is regarded as a significant health problem in 
Ecuador by the Ministry of Health, and the incidence has increased over 
the last years, an official map on the geographic distribution of 
disease and sand fly vectors or a control strategy do not exist yet. 
This article reviews the current situation based on published 
information to improve our knowledge and understand the epidemiological 
situation of leishmaniasis in Ecuador in order to help future research 
and to develop a national control strategy. The disease is endemic in 
most provinces throughout Pacific coastal region, Amazonian lowlands, 
and some inter-Andean valleys with a total 21,805 cases reported during 
1990-2003. Whereas cutaneous leishmaniasis (CL) is found throughout 
Ecuador, mucocutaneous leishmaniasis (MCL) appears to be restricted to 
the Amazon region; one, parasitologically unconfirmed case of visceral 
form was reported in 1949. Most human infections are caused by 
Leishmania (Viannia) spp., which is distributed in the subtropical and 
tropical lowlands; infections due to L. (Leishmania) spp. are found in 
the Andean highlands and in the Pacific lowlands as well. The proven 
vectors are Lutzomyia trapidoi and Lu. ayacuchensis. Canis familiaris, 
Sciurus vulgaris, Potos flavus, and Tamandua tetradactyla have been 
found infected with Leishmania spp. It is estimated that around 3000-
4500 people may be infected every year, and that 3.1 to 4.5 millions 
people are estimated to be at risk of contracting leishmaniasis.




PMID: 15654435
 

TITLE: Antileishmanial activity of lapachol analogues.

AFFILIATION: Departamento de Química, Centro de Ciências Exatas e Naturais,
Universidade Federal de Alagoas, Maceió, AL, 57072-970, Brasil.

REFERENCE: Mem Inst Oswaldo Cruz 2004 Nov 99(7):757-61

The antileishmanial activity of lapachol, isolapachol, and 
dihydrolapachol, along with soluble derivatives (potassium salt) and 
acetate was obtained. All the compounds were assayed against metacyclic 
promastigotes of two different species of Leishmania associated to 
tegumentar leishmaniasis: L. amazonensis and L. braziliensis. All 
compounds presented significant activity, being isolapachol acetate the 
most active against promastigotes, with IC50/24h = 1.6 +/- 0.0 microg/ml
 and 3.4 +/- 0.5 microg/ml for, respectively, L. amazonensis and L. 
braziliensis. This compound was also assayed in vivo against L. 
amazonensis and showed to be active. Its toxicity in vitro was also 
established, and at concentration similar to the IC50, no toxicity was 
evidenced. In all experiments, pentamidine isethionate was used as a 
reference drug. The present results reinforce the potential use of 
substituted hydroxyquinones and derivatives as promising antileishmanial
 drugs and suggest a continuing study within this class of compounds.




PMID: 15378352
 

TITLE: Immune response induced by New World Leishmania species in C57BL/6 mice.

AFFILIATION: Departamento de Ciências Biológicas, Instituto de Ciências
Exatas e Biológicas/NUPEB, Universidade Federal de Ouro Preto, 35400-000, Ouro
Preto, Minas Gerais, Brazil.

REFERENCE: Parasitol Res 2004 Oct 94(3):207-12

In the present study, C57BL/6 mice were inoculated with metacyclic 
Leishmania amazonensis or L. braziliensis promastigotes. While these 
animals were capable of controlling the infection by L. braziliensis, 
they developed chronic lesions with elevated numbers of parasites when 
infected by L. amazonensis. The differences in parasite control were 
associated with a decreased production of IFN-gamma and TNF by lymph 
node cells from L. amazonensis-infected mice. Furthermore, these animals
 presented decreased spleen cell proliferation and activation of 
germinal centers. In addition, we compared the ability of these 
parasites to hydrolyze extracellular ATP and AMP. While the ATPase 
activity of both parasite species was similar, L. amazonensis 
promastigotes presented higher AMP hydrolytic activity. This increased 
activity may lead to an increased production of adenosine, which has 
been shown to present anti-inflammatory activity and may thus be 
involved in the establishment of the immunosuppression observed in mice 
infected by L. amazonensis.




PMID: 15562617
 

TITLE: Quantification of Leishmania infantum parasites in tissue biopsies by
real-time polymerase chain reaction and polymerase chain reaction-enzyme-linked
immunosorbent assay.

AFFILIATION: Unidade de Leishmanioses, Centro Malaria Outras Doenças Tropicais,
Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da
Junqueira 96, 1349-008 Lisbon, Portugal.

REFERENCE: J Parasitol 2004 Oct 90(5):1150-4

Most of the experimental studies of Leishmania spp. infection require 
the determination of the parasite load in different tissues. 
Quantification of parasites by microscopy is not very sensitive and is 
time consuming, whereas culture microtitrations remain laborious and can
 be jeopardized by microbial contamination. The aim of this study was to
 quantify Leishmania infantum parasites by real-time polymerase chain 
reaction (PCR) using specific DNA TaqMan probes and to compare the 
efficacy of detection of this technique with a PCR-enzyme-linked 
immunosorbent assay (ELISA). For this purpose, spleen and liver samples 
from L. infantum-infected mice were collected during a 3-mo longitudinal
 study and analyzed by both methods. PCR-ELISA failed to quantify 
Leishmania spp. DNA in samples with very low or very high numbers of 
parasites. Real-time PCR was more sensitive than PCR-ELISA, detecting 
down to a single parasite, and enabled the parasite quantification over 
a wide, 5-log range. In summary, this study developed a method for 
absolute quantification of L. infantum parasites in infected organs 
using real-time TaqMan PCR.




PMID: 15516635
 

TITLE: Protection of C3HeB/FeJ mice against Leishmania amazonensis challenge
after previous Leishmania major infection.

AFFILIATION: Department of Veterinary Pathology, College of Veterinary Medicine,
Iowa State University, Ames, IA 50011-1250, USA. yannick at iastate.edu

REFERENCE: Am J Trop Med Hyg 2004 Oct 71(4):407-11

The Th1 response elicited in mice infected with Leishmania major has 
been used as a model to characterize cellular immune defects associated 
with L. amazonensis infection. However, it is not known if the immune 
response associated with the infection by virulent L. major parasites 
can promote resistance to a subsequent L. amazonensis infection. Our 
data demonstrate that C3HeB/FeJ mice infected subcutaneously with 
virulent L. major are resistant to an L. amazonensis challenge. The 
healing phenotype is characterized by a Th1 response as measured by 
increased production of interferon-gamma and low levels of interleukin-4
 in the draining lymph node. Together, this indicates that the Th1 
response associated with L. major infection can promote resistance to L
. amazonensis infection and that it can be used as a tool to study the 
immune defects associated with L. amazonensis infection.




PMID: 15338282
 

TITLE: An improved method for detection of Leishmania amastigotes by an antibody
probe against the small subunit of leishmanial ribonucleotide reductase.

AFFILIATION: Division of infectious diseases, Institute of Biomedical Sciences,
Academia Sinica, 11529, Taipei, Taiwan, ROC.

REFERENCE: Parasitol Res 2004 Oct 94(3):243-5

By taking advantage of an antibody raised against the small M2 subunit 
of ribonucleotide reductase of Leishmania that reacts with the enzyme in
 the nucleus of the parasite but does not cross-react with the same 
enzyme of the host macrophage, an improved fluorescence-staining method 
is developed for enumeration of leishmanial amastigotes inside the 
macrophage. The method offers an accurate and easy way of counting, 
compared with Giemsa staining.




PMID: 15364110
 

TITLE: Vaccination with Leishmania soluble antigen and immunostimulatory
oligodeoxynucleotides induces specific immunity and protection against
Leishmania donovani infection.

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

REFERENCE: FEMS Immunol Med Microbiol 2004 Oct 42(2):241-8

In this report, we investigated the effect of ODN containing 
immunostimulatory CG motifs as adjuvant with soluble antigen (SA) from 
Leishmania donovani. BALB/c mice were vaccinated with the soluble 
antigen with or without CpG-ODN as adjuvant and then challenged with L. 
donovani metacyclic promastigotes. CpG-ODN alone resulted in partial 
protection against challenge with L. donovani. Immunization of mice with
 SA and CpG-ODN showed enhanced reduction in parasite load ( 
approximately 60%) when compared to SA ( approximately 40%) immunized 
mice. Immunization with SA by itself resulted in a mixed Th1/Th2 
response whereas co-administration of SA with CpG-ODN resulted in a 
strong Th1 promoting isotype as they together promoted production of 
immunoglobulin G2a. Leishmania-specific Th1 cytokine response was 
induced by co-administering CpG-ODN and SA as they together promoted 
production of IFN-gamma and IL-12. In the present study, we demonstrate 
that immunostimulatory phosphorothioate-modified ODN are promising 
immune enhancers for vaccination against visceral leishmaniaisis.




PMID: 15466622
 

TITLE: A subset of liver NK T cells is activated during Leishmania donovani
infection by CD1d-bound lipophosphoglycan.

AFFILIATION: Department of Medicine, Weill College of Medicine, Cornell
University, New York, NY 10021, USA.

REFERENCE: J Exp Med 2004 Oct 200(7):895-904

Natural killer (NK) T cells are activated by synthetic or self-
glycolipids and implicated in innate host resistance to a range of viral
, bacterial, and protozoan pathogens. Despite the immunogenicity of 
microbial lipoglycans and their promiscuous binding to CD1d, no pathogen
-derived glycolipid antigen presented by this pathway has been 
identified to date. In the current work, we show increased 
susceptibility of NK T cell-deficient CD1d(-/-) mice to Leishmania 
donovani infection and Leishmania-induced CD1d-dependent activation of 
NK T cells in wild-type animals. The elicited response was Th1 polarized
, occurred as early as 2 h after infection, and was independent from IL-
12. The Leishmania surface glycoconjugate lipophosphoglycan, as well as 
related glycoinositol phospholipids, bound with high affinity to CD1d 
and induced a CD1d-dependent IFNgamma response in naive intrahepatic 
lymphocytes. Together, these data identify Leishmania surface 
glycoconjugates as potential glycolipid antigens and suggest an 
important role for the CD1d-NK T cell immune axis in the early response 
to visceral Leishmania infection.




PMID: 15448686
 

TITLE: Central memory T cells mediate long-term immunity to Leishmania major in
the absence of persistent parasites.

AFFILIATION: Department of Pathobiology, University of Pennsylvania, 3800 Spruce
Street, Philadelphia, Pennsylvania 19104, USA.

REFERENCE: Nat Med 2004 Oct 10(10):1104-10

Infection with Leishmania major induces a protective immune response and
 long-term resistance to reinfection, which is thought to depend upon 
persistent parasites. Here we demonstrate that although effector CD4(+) 
T cells are lost in the absence of parasites, central memory CD4(+) T 
cells are maintained. Upon secondary infection, these central memory T 
cells become tissue-homing effector T cells and mediate protection. Thus
, immunity to L. major is mediated by at least two distinct populations 
of CD4(+) T cells: short-lived pathogen-dependent effector cells and 
long-lived pathogen-independent central memory cells. These data suggest
 that central memory T cells should be the targets for nonlive vaccines 
against infectious diseases requiring cell-mediated immunity.




PMID: 15459703
 

TITLE: Memory may not need reminding.

REFERENCE: Nat Med 2004 Oct 10(10):1045-7




PMID: 15301978
 

TITLE: Detection of high rates of in-village transmission of Leishmania donovani
in eastern Sudan.

AFFILIATION: Department of Zoology, Faculty of Science, University of Khartoum,
P. O. Box 321, Khartoum, Sudan.

REFERENCE: Acta Trop 2004 Sep 92(1):77-82




PMID: 15476431
 

TITLE: [Visceral leishmaniasys in an immunocompetent patient: an entity to be
considered in the differential diagnosis of fever of unknown origin]

REFERENCE: An Med Interna 2004 Sep 21(9):466




PMID: 15270599
 

TITLE: Leishmania in the glomerulus.

AFFILIATION: Department of Pathology, Shiraz Medical School, Shiraz University
of Medical Sciences, Shiraz, Iran. Kumarv at sums.ac.ir

REFERENCE: Arch Pathol Lab Med 2004 Aug 128(8):935-6




PMID: 15372989
 

TITLE: Plasma thrombomodulin levels in dogs naturally infected with Leishmania
infantum.

AFFILIATION: Department of Veterinary Clinical Science--Section of Internal
Medicine--University of Naples Federico II, via Delpino, 1--80137 Naples,
Italy. paociara at unina.it

REFERENCE: Vet Res Commun 2004 Aug 28 Suppl 1():327-30




PMID: 15372990
 

TITLE: Haemostatic disorders in dogs naturally infected by Leishmania infantum.

AFFILIATION: Department of Veterinary Clinical Science--Section of Internal
Medicine, University of Naples, Italy.

REFERENCE: Vet Res Commun 2004 Aug 28 Suppl 1():331-4




PMID: 15379431
 

TITLE: Canine visceral leishmaniosis in Anastácio, Mato Grosso do Sul state,
Brazil.

AFFILIATION: Departamento de Patologia, Laboratório de Parasitologia Humana,
Universidade Federal de Mato Grosso do Sul, Brazil.

REFERENCE: Vet Res Commun 2004 Jul 28(5):365-74

Canine visceral leishmaniosis (CVL) may be an important factor preceding
 human outbreaks of the disease. We report that the prevalence of canine
 visceral leishmaniosis infection has been increasing in recent years in
 Anastácio town, located in the central western region of Brazil. 
Serological investigations showed that 75.3% of dogs presented antibody 
titres ranging from 1/40 to 1/160 in the indirect immunofluorescence 
antibody test (IFAT). Bone marrow and lymph node aspirates provided 
positive cultures and furnished parasites for enzymological and 
serological typing in 42.5% and 41.1% of the cases, respectively. All 
the strains were typed as Leishmania (L.) chagasi. This is primarily a 
canine disease that spills over into the human population as a zoonosis
. The study showed the epidemiological features of the infection in a 
region in which the problem of visceral leishmaniosis has been 
underestimated.




PMID: 15284686
 

TITLE: Sensitivity of splenic and bone marrow aspirate study for diagnosis of
kala-azar.

AFFILIATION: Department of Medicine, Mymensingh Medical College, Mymensingh,
Bangladesh. cnsarker at yahoo.com, cnsarker at bttb.net.bd

REFERENCE: Mymensingh Med J 2004 Jul 13(2):130-3

Fifty adult patients of kala-azar were included in this prospective 
study from Medicine Unit-I of Mymensingh Medical College Hospital. 
Splenic and bone marrow aspiration were done simultaneously to compare 
the sensitivity and other related merits and demerits of each procedure
. Splenic aspiration appeared to be more sensitive procedure than bone 
marrow aspiration. Leishman - Donovan (LD) bodies were found in 90 
percent and 72 percent of the spleen and bone marrow aspirates 
respectively. Splenic aspiration was found more acceptable to patients (
96%) as it was less painful. Both the procedures were hazardless. There 
was no major complication except mild pain after splenic aspiration; 
even a few patients had history of epistaxis. Splenic aspiration was 
also more acceptable by the physicians because of an easy and reliable 
diagnostic procedure.




PMID: 15273802
 

TITLE: Leishmania braziliensis: partial control of experimental infection by
interleukin-12 p40 deficient mice.

AFFILIATION: Departamento de Ciências Biológicas, Instituto de Ciências
Exatas e Biológicas, Brasil.

REFERENCE: Mem Inst Oswaldo Cruz 2004 May 99(3):289-94

Resistance to infection by Leishmania major has been associated with the
 development of a Th1 type response that is dependent on the presence of
 interleukin 12 (IL-12). In this work the involvement of this cytokine 
in the response to infection by L. braziliensis, a less virulent species
 in the mouse model, was evaluated. Our results show that while 
interferon (IFN-gamma) deficient (-/-) mice inoculated L. braziliensis 
develop severe uncontrolled lesions, chronic lesions that remained under
 control up to 12 weeks of infection were observed in IL-12p40 -/- mice
. IL 12p40 -/- mice had fewer parasites in their lesions than IFN-gamma
 (-/-) mice. Lymph node cells from IL-12p40 -/- were capable of 
producing low but consistent levels of IFN-gamma suggestive of its 
involvement in parasite control. Furthermore, as opposed to previous 
reports on L. major-infected animals, no switch to a Th2 response was 
observed in IL-12p40 -/- infected with L. braziliensis.




PMID: 15250479
 

TITLE: Evaluation of cholinesterase level in an endemic population exposed to
malathion suspension formulation as a vector control measure.

AFFILIATION: Rajendra Memorial Research Institute of Medical Sciences, (Indian
Council of Medical Research), Patna 800 007, India. drcslal at sify.com

REFERENCE: Mem Inst Oswaldo Cruz 2004 Mar 99(2):219-21

The manuscript describes a study on the blood cholinesterase (ChE) level
 in an exposed population at different interval of time after spraying 
with malathion suspension (SRES) use for kala-azar vector control in an 
endemic area of Bihar, India. The toxicity of a 5% malathion formulation
 in the form of a slow release emulsified suspension (SRES) was assessed
 by measuring serum ChE levels in spraymen and in the exposed population
. The study showed a significant decrease in ChE levels in the spraymen
 (p < 0.01) after one week of spraying and in exposed population one 
week and one month after of spraying (p < 0.01), but was still within
 the normal range of ChE concentration, one year after spraying, the ChE
 concentration in the exposed population was the same as prior to 
spraying (p > 0.01). On no occasion was the decrease in ChE level 
alarming. A parallel examination of the clinical status also showed the 
absence of any over toxicity or any behavioural changes in the exposed 
population. Hence, it may be concluded that 5% malathion slow release 
formulation, SRES, is a safe insecticide for use as a vector control 
measure in endemic areas of kala-azar in Bihar, India so long as good 
personal protection for spraymen is provided to minimize absorption and 
it can substitute the presently used traditional DDT spray.




PMID: 15541032
 

TITLE: Adjuvant guided polarization of the immune humoral response against a
protective multicomponent antigenic protein (Q) from Leishmania infantum. A CpG
+ Q mix protects Balb/c mice from infection.

AFFILIATION: Centro de Biología Molecular, CSIC-UAM, Canto Blanco, Madrid,
Spain.

REFERENCE: Parasite Immunol 2004 Jun-Jul 26(6-7):283-93

It has been shown that vaccination with three doses of the Leishmania 
infantum poly-protein Q containing five genetically fused antigenic 
determinants from the Lip2a, Lip2b, H2A and P0 proteins, mixed with BCG 
induces clearance of parasites in 9 out of 10 Leishmania infantum-
infected Beagle dogs, in addition to clinical protection. In the present
 paper we analysed the immunogenic potential of the poly-protein Q and 
the specificity and polarization of the response against the antigenic 
determinants of Q when mixed with various adjuvants. The data showed 
that the Q protein had high intrinsic immunogenic potential and that it 
was able to induce a long-lasting IgG response. The IgM immunogenic 
potential of the poly-protein was mainly due to the LiP2a and LiP2b 
determinants, whereas the IgG immunogenic potential was mainly due to 
the LiP2a component. It was observed that the protein itself elicited a 
mixed IgG2a/IgG1 response and that the determinants of Q were endowed 
with different IgG2a/IgG1 potential. It was also observed that the 
adjuvants did not influence the intensity or specificity of the IgM 
response but that they modulated the intensity, the specificity and the 
polarization of the IgG response against the determinants of Q. CpG-ODN 
motifs or double-stranded DNA plasmids containing CpG motifs when mixed 
with Q induced a predominant IgG2a response mainly observed at early 
stages post-immunization. The data showed that a CpG + Q mix induced 
significant protection against L. infantum infection in Balb/c mice.








PMID: 15515575
 

TITLE: Free light-chain proteinuria and normal renal histopathology and function
in 11 dogs exposed to Lleishmania infantum, Ehrlichia canis, and Bbabesia
canis.

AFFILIATION: Clinica Veterinaria Gran Sasso, Milano, Italy. u.bonfa at flashnet.it

REFERENCE: J Vet Intern Med 2004 Sep-Oct 18(5):618-24

The purpose of this retrospective study was to investigate the 
relationship among proteinuria consisting of immunoglobulin free light 
chains (FLCs), renal histopathologic findings, and routine markers of 
renal function in 11 dogs exposed to Leishmania infantum (n = 8), 
Ehrlichia canis (n = 2), and Babesia canis (n = 1). FLC proteinuria was 
suspected based on identification of a 22- to 27-kDa band by sodium 
dodecyl sulfate-agarose gel electrophoresis (SDS-AGE) and later 
confirmed by immunofixation electrophoresis. SDS-AGE identified an 
isolated band of 22-27 kDa in 8 dogs, whereas the remaining 3 had a 22- 
to 27-kDa band and an additional band of 67-72 kDa. The median urine 
protein-to-urine creatinine ratio was 0.37 (range, 0.11-2.24) and 
increased ratios were found in 6 dogs (54.5%) (reference value, <0.7
). All dogs underwent histologic examination of renal percutaneous 
biopsy specimens and determination of serum creatinine and urea 
concentrations. Tissue samples for light microscopy were stained with 
hematoxylin-eosin, periodic acid-Schiff, Goldners trichrome, and 
methenamine silver. In the study group, the glomerular tufts, mesangium
, tubulointerstitium, and vessels appeared unaffected. The median serum 
creatinine concentration in these 11 dogs was 1.3 mg/dL (range, 0.8-1.5 
mg/dL; reference range, 0.6-1.5 mg/dL), whereas the concentration for 
urea was 28 mg/dL (range, 22-52 mg/dL; reference range, 20-50 mg/dL). 
All dogs had normal renal morphology and had normal serum creatinine and
 urea concentrations, suggesting that immunoglobulin FLC may be detected
 in the urine of dogs exposed to L. infantum, E. canis, and B. canis 
without any apparent structural or functional renal derangement.




PMID: 15621670
 

TITLE: Amphotericin B molecular organization as an essential factor to improve
activity/toxicity ratio in the treatment of visceral leishmaniasis.

REFERENCE: J Drug Target 2004  12(7):453-60

An in vivo study has been performed in order to determine the influence 
of amphotericin B (AMB) molecular organization on the toxicity and 
activity of this drug in the treatment of experimental visceral 
leishmaniasis. Three formulations with similar composition but different
 drug molecular self-association in aqueous media were prepared. Acute 
toxicity was evaluated by injecting them in healthy hamsters. Sub-acute 
toxicity and efficacy were studied administering them to animals 
previously infected with Leishmania infantum. The preparation with drug 
molecules completely dissolved into monomers (formulation "C&quot
;) and produced the highest acute toxicity. The formulation whose AMB 
molecules were disposed as non-water-soluble multi-aggregates (
formulation "B") proved to provide the lowest acute toxicity. 
This formula also showed an improved activity, mainly in the liver, if 
compared with the third tested formulation containing AMB molecules 
disposed as smaller dimerical "water-soluble" aggregates (
formulation "A"). As a conclusion, molecular aggregation in 
biological media should be an important factor to consider when 
researching or optimizing medicines containing AMB. The liberation of 
molecules as large dispersed non-water-soluble multi-aggregates seems to
 improve the narrow therapeutic margin attached to the use of this drug.




PMID: 15491550
 

TITLE: Leishmania (Viannia): genetic analysis of cutaneous and mucosal strains
isolated from the same patient.

AFFILIATION: Department of Tropical Medicine, Oswaldo Cruz Institute, FIOCRUZ,
Rio de Janeiro, Brazil.

REFERENCE: Exp Parasitol 2004 Sep-Oct 108(1-2):59-66

Ten pairs of Leishmania (Viannia) strains isolated from mucosal and 
cutaneous lesions of the same patient were analyzed genotypically in 
order to determine whether populations that had metastasized to mucosal 
sites differed from those in the cutaneous lesion. The strains were 
previously characterized by multi locus enzyme electrophoresis and/or 
monoclonal antibodies reactivity, and, for this study, only isolates 
from the same patient which were identified as the same species were 
employed. PCR-RFLP of internal transcribed spacer (ITS) rDNA, random 
amplified polymorphic DNA (RAPD), and schizodeme analyses were conducted
. All genotyping methods revealed microheterogeneity between cutaneous 
and mucosal isolates from the same patient. The PCR-RFLP of the ITS rDNA
 and RAPD analysis were numerically analyzed through similarity 
coefficients and dendrograms were generated. All phenograms clustered 
cutaneous and mucosal strains of the same patient in one branch with a 
high degree of similarity, and phenetic analysis matched between them. 
Schizodeme analysis revealed differences between strains that composed 
some pairs. Genetic analyses indicate that some populations that 
metastasize to mucosal sites are distinguishable from the population in 
cutaneous lesions, however, other approaches will be required to 
associate genetic polymorphisms with the cutaneous or mucosal phenotype 
of strains.




PMID: 15597297
 

TITLE: Fever of unknown origin caused by adult juvenile rheumatoid arthritis:
The diagnostic significance of double quotidian fevers and elevated serum
ferritin levels.

REFERENCE: Heart Lung 2004 Nov-Dec 33(6):417-21

Fever of unknown origin (FUO) in adults is a commonly encountered 
clinical problem. Treatable causes of FUO in the adult should be the 
primary focus of the diagnostic workup. Neoplasms have replaced 
infectious diseases as being the most common cause of FUO in adults, and
 collagen vascular diseases are now relatively rare. The most important 
collagen vascular diseases presenting as an FUO include Takayasu's 
arteritis, Kikuchi's disease, polymyalgia rheumatica, and adult juvenile
 rheumatoid arthritis (JRA) (adult Still's disease). There are no 
specific diagnostic tests for these disorders, which commonly present as
 prolonged fevers that are not easily diagnosed (i.e., FUO). Adult JRA 
is a rare but important cause of FUO in adults. Typically, patients with
 adult Still's disease present with liver/spleen involvement, posi-
articular arthritis, ocular involvement, and evanescent salmon-colored 
truncal rash. An important diagnostic finding in adult JRA is the 
presence of a double quotidian fever, which occurs in few other 
disorders. Only visceral leishmaniasis and adult JRA are causes of FUO 
in adults associated with double quotidian fevers. Highly elevated serum
 ferritin levels are the most important nonspecific diagnostic finding 
associated with adult JRA. We present a case of FUO caused by adult JRA 
presenting with diffuse polyarticular migrating arthritis, evanescent 
rash, and splenomegaly. The diagnosis of adult JRA was suggested by 
these findings in association with a double quotidian fever and a highly
 elevated serum ferritin level. Clinicians should appreciate the 
diagnostic significance of fever patterns and the diagnostic 
significance of elevated serum ferritin levels in patients with FUO.




PMID: 15615393
 

TITLE: [Detection of Leishmania infantum MON-24 in the dog]

AFFILIATION: Service de Parasitologie-Mycologie, Institut Pasteur d'Algérie,
Alger, Algérie. rbenikhlef at yahoo.fr

REFERENCE: Med Trop (Mars) 2004  64(4):381-3

Two forms of cutaneous leishmaniasis are endemic in Algeria. Zoonotic 
cutaneous leishmaniasis caused by Leishmania major is widespread in the 
steppe regions of the northern Sahara. Sporadic cutaneous leishmaniasis 
caused by Leishmania infantum occurs in the north along the coastline. 
The main causative agent for the sporadic form is Leishmania infantum 
zymodeme MON-24. It has been isolated from the sandfly vector 
Phlebotomus perfiliewi. However all attempts to isolate this variant 
from dogs, i.e., the main reservoir of Leishmania infantum, have failed
. The authors report the first successful detection of Leishmania 
infantum MON-24 in the dog.




PMID: 15615399
 

TITLE: [Alithiasic cholecystitis in association with visceral leishmaniasis in
an immunodepressed patient]

REFERENCE: Med Trop (Mars) 2004  64(4):407-8




PMID: 15571500
 

TITLE: Treatment of protozoan infections.

AFFILIATION: Center for Clinical Studies, Houston, TX.

REFERENCE: Dermatol Ther 2004  17(6):513-6

Protozoan infections can have a variety of different cutaneous 
manifestations in addition to systemic signs and symptoms of disease. 
Recognition and diagnosis can be difficult, as additional laboratory 
tests, in addition to biopsies, may be required. Treatment options for 
different protozoa vary and resolution of disease may be refractory 
despite lengthy treatment courses. An overview of cutaneous 
manifestations, diagnosis, and treatment regimen of amebiasis, 
leishmaniasis, trypanosomiasis, and toxoplasmosis is outlined in this 
article.




PMID: 12951545
 

TITLE: Concurrent infections that rise the HIV viral load.

AFFILIATION: Department of Immunology and Microbiology, Ben Gurion University
Health Sciences Faculty, Beer Sheba, Israel. zvibent at netvision.net.il

REFERENCE: J HIV Ther 2003 Aug 8(3):72-5

A common denominator of all the major infections found concurrently with
 HIV is immune activation. Though the type and characteristics of this 
activation differ among the various infections, the result is invariably
 increased HIV infection and replication. Furthermore, the immune 
activation may affect other concurrent infections such as tuberculosis. 
Therefore, eradication or suppression of concurrent infections in HIV-
infected people may have a major impact on the spread and progression of
 HIV infection and AIDS, and also on protective HIV vaccines. This 
applies particularly to developing countries, where these infections are
 common and no antiretroviral therapy is available. Further studies are 
urgently needed to clarify and further characterise the long-term 
effects of concurrent infections on the spread and progression of HIV/
AIDS, and particularly on the immune response of the infected host.




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PMID: 15187137
 

TITLE: Protection against progressive leishmaniasis by IFN-beta.

AFFILIATION: Institute of Clinical Microbiology, Immunology and Hygiene,
University of Erlangen-Nuremberg, Erlangen, Germany.

REFERENCE: J Immunol 2004 Jun 172(12):7574-82

Type I IFNs (IFN-alphabeta) exert potent antiviral and immunoregulatory 
activities during viral infections, but their role in bacterial or 
protozoan infections is poorly understood. In this study, we demonstrate
 that the application of low, but not of high doses of IFN-beta protects
 60 or 100% of BALB/c mice from progressive cutaneous and fatal visceral
 disease after infection with a high (10(6)) or low (10(4)) number of 
Leishmania major parasites, respectively. IFN-beta treatment of BALB/c 
mice restored the NK cell cytotoxic activity, increased the lymphocyte 
proliferation, and augmented the production of IFN-gamma and IL-12 in 
the draining lymph node. Low, but not high doses of IFN-beta caused 
enhanced tyrosine phosphorylation of STAT1 and STAT4, suppressed the 
levels of suppressor of cytokine signaling-1, and up-regulated the 
expression of inducible NO synthase in vivo. The IFN-beta-induced 
increase of IFN-gamma production was dependent on STAT4. Protection by 
IFN-beta strictly required the presence of inducible NO synthase. In the
 absence of STAT4 or IL-12, IFN-beta led to an amelioration of the 
cutaneous and visceral disease, but was unable to prevent its 
progression. These results identify IFN-beta as a novel cytokine with a 
strong, dose-dependent protective effect against progressive cutaneous 
leishmaniasis that results from IL-12- and STAT4-dependent as well as -
independent events.




PMID: 15482193
 

TITLE: Progress in the treatment of a neglected infectious disease: visceral
leishmaniasis.

AFFILIATION: Department of Medicine, Weill Medical College of Cornell
University, 1300 York Avenue, New York, NY 10021, USA.
hmurray at med.cornell.edu.

REFERENCE: Expert Rev Anti Infect Ther 2004 Apr 2(2):279-92

Visceral leishmaniasis (kala-azar) is a disseminated intracellular 
protozoal infection. Most cases (90%) occur in the rural regions of five
 countries: India, Sudan, Nepal, Bangladesh and Brazil. As with other 
infectious diseases embedded in high-level poverty, developing and/or 
delivering new treatments for visceral leishmaniasis had been painfully 
slow or nonexistent. However, despite persistent unresolved obstacles (e
.g., drug affordability), renewed interest in visceral leishmaniasis and
 numerous successful treatment trials have combined to turn a 
therapeutic corner in the past 5 years, yielding new alternatives to 
conventional pentavalent antimony. Advances include the use of low-cost 
generic pentavalent antimony, rediscovery of amphotericin B, short-
course regimens via lipid formulations of amphotericin B, retesting 
injectible paromyomycin and, of clear-cut importance, identifying 
miltefosine (Impavido, Zentaris) as the first effective oral therapy for
 this neglected disease.




PMID: 15035723
 

TITLE: A comparative evaluation of amphotericin B and sodium antimony gluconate,
as first-line drugs in the treatment of Indian visceral leishmaniasis.

AFFILIATION: Balaji Utthan Sansthan, Uma Complex, Fraser Road, Patna - 800 001,
India. cpthakur at sancharnet.in

REFERENCE: Ann Trop Med Parasitol 2004 Mar 98(2):129-38

In a study to evaluate the relative efficacies of sodium antimony 
gluconate (SAG) and amphotericin B (AMB), each drug was used to treat 60
 Indian cases of visceral leishmaniasis (VL). At the time of treatment, 
each case had recently been parasitologically confirmed. The patients 
received either 20 mg SAG/kg daily, by intramuscular injection, for 4 
weeks, or 1 mg AMB/kg daily, infused slowly over 2 h, with no 
incremental dosage, for 20 days. The response of the patients was 
followed clinically and by the microscopical examination of bone-marrow 
aspirates (BMA). The infected macrophages in subsamples of the BMA 
collected pre-treatment were cultured so that the drug sensitivities of 
the parasites, to 20 microg SAG or 1 microg AMB/ml medium, could be 
determined in vitro. Other subsamples of the BMA were used to set up 
promastigote cultures that were then used to infect BALB/c mice. The 
responses of the mice to 5 days of treatment with SAG or AMB (at the 
same daily dosages as used in the clinical trials) were subsequently 
explored. SAG only cured 46.6% of the patients given the drug, only 
cleared amastigotes from 38.3% of the macrophage cultures, and only 
cured 53.3% of the infected mice. The corresponding values for AMB - 100
%, 100% and 100% - were markedly higher (P <0.001 for each comparison
). Although nine patients had to be withdrawn from the SAG group (all 
because of cardiac toxicity), all of the patients given AMB completed 
their treatment without any serious adverse effects (P <0.01). Two of
 the patients withdrawn from the SAG arm died shortly after their 
withdrawal; earlier withdrawal may have saved them. At least in the 
setting of the present study, AMB appears far superior to SAG as a first
-line drug against VL and should replace it.




PMID: 14991601
 

TITLE: Two waves of antigen-containing dendritic cells in vivo in experimental
Leishmania major infection.

AFFILIATION: Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare
Biologie, Berlin, Germany.

REFERENCE: Eur J Immunol 2004 Mar 34(3):715-25

Dendritic cells (DC) can induce Th1 cell differentiation by producing IL
-12. In experimental infection with Leishmania major, DC could 
differently respond to infection and induce Th1 cells in C57BL/6 but not
 BALB/c mice, and thus determine the resistance or susceptibility of 
these mice. We characterized L. major antigen-containing DC in vivo in 
draining lymph nodes of both strains. Conventional experimental 
infection is shown to result in two waves of these DC and our data argue
 against a relevant genetic difference in the DC initiating the anti-
parasite Th cell response in these mice. In both strains the first wave 
of DC presented L. major antigens but was not infected, produced IL-12 
but induced disease-mediating Th2 cells upon adoptive transfer. In 
contrast to current belief, this response was therefore not initiated by
 infected DC, which were only detected in the second wave. The kinetics 
of the two waves suggests that DC turnover has an important impact on 
antigen presentation during infections with complex pathogens.




PMID: 15009885
 

TITLE: Localization and activity of multidrug resistance protein 1 in the
secretory pathway of Leishmania parasites.

AFFILIATION: Department of Immunology and Infectious Diseases, Harvard School of
Public Health, Boston, MA 02115, USA.

REFERENCE: Mol Microbiol 2004 Mar 51(6):1563-75

Upregulation of the multidrug resistance protein 1 (LeMDR1) in the 
protozoan parasite, Leishmania enriettii, confers resistance to 
hydrophobic drugs such as vinblastine, but increases the sensitivity of 
these parasites to the mitochondrial drug, rhodamine 123. In order to 
investigate the mechanism of action of LeMDR1, the subcellular 
localization of green fluorescent protein (GFP)-tagged versions of 
LeMDR1 and the fate of the traceable-fluorescent LeMDR1 substrate 
calcein AM were examined in both Leishmania mexicana and L. enriettii 
LeMDR1 -/- and overexpressing cell lines. The LeMDR1-GFP chimera was 
localized by fluorescence microscopy to a number of secretory and 
endocytic compartments, including the Golgi apparatus, endoplasmic 
reticulum (ER) and a multivesicular tubule (MVT)-lysosome. Pulse-chase 
labelling experiments with calcein AM suggested that the Golgi and ER 
pools, but not the MVT-lysosome pool, of LeMDR1 were active in pumping 
calcein AM out of the cell. Cells labelled with calcein AM under 
conditions that slow vesicular transport (low temperature and stationary
 growth) inhibited export and resulted in the accumulation of 
fluorescent calcein in both the Golgi and the mitochondria. We propose 
that LeMDR1 substrates are pumped into secretory compartments and 
exported from the parasite by exocytosis. Accumulation of MDR substrates
 in the ER can result in alternative transport to the mitochondrion, 
explaining the reciprocal sensitivity of drug-resistant Leishmania to 
vinblastine and rhodamine 123.




PMID: 15009450
 

TITLE: Natural breeding places of phlebotomine sandflies.

AFFILIATION: Universidad de Carabobo, Facultad de Ciencias de la Salud, Centro
Nacional de Referencia de Flebótomos, BIOMED, Núcleo Aragua, Maracay,
Venezuela. mdora at telcel.vet.ve

REFERENCE: Med Vet Entomol 2004 Mar 18(1):71-80

Methods of finding larvae and pupae of phlebotomine sandflies (Diptera: 
Psychodidae) are described and the known types of breeding sites used by
 sandflies are listed. Three ways of detecting sandfly breeding places 
are the use of emergence traps placed over potential sources to catch 
newly emerged adult sandflies; flotation of larvae and pupae from soil, 
etc., and desiccation of media to drive out the larvae. Even so, 
remarkably little information is available on the ecology of the 
developmental stages of sandflies, despite their importance as vectors 
of Leishmania, Bartonella and phleboviruses affecting humans and other 
vertebrates in warmers parts of the world. Regarding the proven or 
suspected vectors of leishmaniases, information on breeding sites is 
available for only 15 out of 29 species of sandflies involved in the Old
 World and 12 out of 44 species of sandflies involved in the Americas, 
representing approximately 3% of the known species of Phlebotominae. 
Ecotopes occupied by immature phlebotomines are usually organically rich
 moist soils, such as the rain forest floor (Lutzomyia intermedia, Lu. 
umbratilis, Lu. whitmani in the Amazon; Lu. gomezi, Lu. panamensis, Lu. 
trapidoi in Panama), or contaminated soil of animal shelters (Lu. 
longipalpis s.l. in South America, Phlebotomus argentipes in India; P. 
chinensis in China; P. ariasi, P. perfiliewi, P. perniciosus in Europe
). Developmental stages of some species (P. langeroni and P. martini in 
Africa; P. papatasi in Eurasia; Lu. longipalpis s.l. in South America), 
have been found in a wide range of ecotopes, and many species of 
sandflies employ rodent burrows as breeding sites, although the 
importance of this niche is unclear. Larvae of some phlebotomines have 
been found in what appear to be specialized niches such as Lu. ovallesi 
on buttress roots of trees in Panama; P. celiae in termite hills in 
Kenya; P. longipes and P. pedifer in caves and among rocks in East 
Africa. Old World species found as immatures in the earthen floor of 
human habitations include P. argentipes, P. chinensis, P. martini and P
. papatasi. Much more information on sandfly breeding sites is required 
to facilitate their control by source reduction.




PMID: 15225226
 

TITLE: Deep sinus aspergillosis in a liver transplant recipient successfully
treated with a combination of caspofungin and voriconazole.

AFFILIATION: Academic Department of Medicine, Hippokration General Hospital, 114
Vas. Sofias Avenue, Athens, Greece.

REFERENCE: Transpl Infect Dis 2004 Mar 6(1):37-40

We describe the rare case of a diabetic patient who was successfully 
treated for cytomegalovirus viremia and leishmaniasis following liver 
transplantation for hepatitis C virus-related cirrhosis, but also 
developed invasive sinus Aspergillus infection, while still on liposomal
 amphotericin B (AmBisome). The patient refused radical surgery 
including eye enucleation, and received a combination of intravenous 
caspofungin and voriconazole, along with repeated, conservative, local 
surgical debridement. At follow-up, 15 months after the onset of 
sinusitis, the patient remains culture-negative, fully active, and 
without evidence of local recurrence.




PMID: 14768057
 

TITLE: Control of Leishmania major in the absence of Tyk2 kinase.

AFFILIATION: Institute of Clinical Microbiology, Immunology and Hygiene,
University of Erlangen-Nuremberg, Erlangen, Germany.

REFERENCE: Eur J Immunol 2004 Feb 34(2):519-29

IL-12 is indispensable for the control of many intracellular pathogens, 
but the components of the signaling pathway that are essential for its 
function in vivo are incompletely understood. Here, we investigated in 
the Leishmania major mouse model whether Tyk2 kinase is required for the
 generation of a protective immune response. Unlike C57BL/6 controls, 
Tyk2(-/-)mice developed severe skin lesions after infection that 
frequently ulcerated, but ultimately healed. NK cell cytotoxicity was 
absent in infected Tyk2(-/-) mice, even after IL-12 pretreatment, which 
correlated with a STAT4 activation defect. IFN-alpha / beta, which was 
still able to activate STAT1 in Tyk2(-/-) NK cells, reconstituted their 
cytotoxic activity, but not their IL-12 responsiveness. The IL-12-
induced production of IFN-gamma by NK cells and CD8(+) T cells was 
strongly suppressed in Tyk2(-/-) mice at day 1 of infection, but partly 
regained during the late phase of infection. Tyk2(-/-) CD4(+) T cells 
developed into Th1 cells (although in a delayed fashion) and infected 
Tyk2(-/-) mice expressed normals levels of inducible NO synthase. Thus, 
Tyk2 is required for the IL-12 response of NK cells and CD8(+) T cells 
in L. major-infected mice, but not for the generation of Th1 cells and 
the ultimate control of the disease.




PMID: 15107544
 

TITLE: Modulation of the immune system by Listeria monocytogenes-mediated gene
transfer into mammalian cells.

AFFILIATION: Department of Immunology and Host Defenses, Ehime University School
of Medicine, Japan.

REFERENCE: Microbiol Immunol 2004  48(4):329-37

In this study, we established a method for Listeria monocytogenes(Lm)-
mediated gene transfer into mammalian cells to manipulate the immune 
response of the host during infection by pathogens. We used the Lm-
mediated gene transfer method in an in vivo study to manipulate host 
immune responses against Leishmania major(L. major )-infection. The 
injection of Lm modulated the susceptible host into a resistant state 
against L. major-infection. A more efficient protective effect was 
obtained with the injection of IL-12-cDNA containing Lm, and the 
protective effect was stronger than that of the resistant strain. The 
protective mechanism of Lm-injection against L. major-infection observed
 here appeared to be a result of the activation of the local immune 
system by the Lm-mediated gene transfer method. The present study is the
 first demonstration that a gene introduced into a host by Lm works to 
modulate the murine host immune response against infections in vivo. 
Since this system strongly induces Th1 responses and suppresses Th2 
responses in infected hosts, the system can be used for controlling 
infectious diseases and for protection against allergic responses in the
 future.




PMID: 14514670
 

TITLE: Functional cloning of the miltefosine transporter. A novel P-type
phospholipid translocase from Leishmania involved in drug resistance.

AFFILIATION: Instituto de Parasitología y Biomedicina López-Neyra, Consejo
Superior de Investigaciones Científicas, 18001 Granada, Spain.

REFERENCE: J Biol Chem 2003 Dec 278(50):49965-71

The antitumor drug miltefosine (hexadecylphosphocholine, MIL) has 
recently been approved as the first oral agent for the treatment of 
visceral leishmaniasis. Little is known about the mechanisms of action 
and uptake of MIL in either parasites or tumor cell lines. We have 
cloned a putative MIL transporter (LdMT) by functional rescue, using a 
Leishmania donovani-resistant line defective in the inward-directed 
translocation of both MIL and glycerophospholipids. LdMT is a novel P-
type ATPase belonging to the partially characterized aminophospholipid 
translocase subfamily. Resistant parasites transfected with LdMT regain 
their sensitivity to MIL and edelfosine and the ability to normally take
 up [14C]MIL and fluorescent-labeled glycerophospholipids. Moreover, 
LdMT localizes to the plasma membrane, and its overexpression in 
Leishmania tarentolae, a species non-sensitive to MIL, significantly 
increases the uptake of [14C]MIL, strongly suggesting that this protein 
behaves as a true translocase. Finally, both LdMT-resistant alleles 
encompass single but distinct point mutations, each of which impairs 
transport function, explaining the resistant phenotype. These results 
demonstrate biochemically and genetically the direct involvement of LdMT
 in MIL and phospholipids translocation in Leishmania and describe for 
the first time a P-type ATPase involved in MIL uptake and potency in 
eukaryotic cells.




PMID: 14573634
 

TITLE: Differential production of macrophage inflammatory protein 1gamma
(MIP-1gamma), lymphotactin, and MIP-2 by CD4(+) Th subsets polarized in vitro
and in vivo.

AFFILIATION: Institute for Medical Microbiology and Hygiene, University of
Lübeck, Lübeck, Germany.

REFERENCE: Infect Immun 2003 Nov 71(11):6178-83

Due to differential expression of chemokine receptors, the Th1 and Th2 
subsets of CD4(+) T cells differ in their migratory responses to 
chemokines. These differences in the migration patterns are likely to 
play a role in the initiation and regulation of Th1 and Th2 immune 
responses, inflammatory processes, and T-cell-mediated pathology. In the
 present study we evaluated the role of activated Th cells as producers 
of chemokines. Three different sources of murine Th cells were used, i.e
., long-term-cultured Th1 and Th2 cell clones, Th1 and Th2 cells 
differentiated from naïve CD4(+) spleen and lymph node cells in vitro, 
and Th1 and Th2 subsets polarized in vivo using a murine experimental 
Leishmania major infection model. Following stimulation with anti-CD3, 
macrophage inflammatory protein 1gamma (MIP-1gamma) and lymphotactin 
were produced selectively by Th1 cells but not by Th2 cells. In contrast
, only Th2 cells produced MIP-2. The possible biological relevance of 
these data was substantiated by the finding that in vivo-polarized Th1 
cells, but not Th2 cells, produced MIP-1gamma and lymphotactin while in 
vivo-polarized Th2 cells secreted MIP-2. The above data demonstrate that
 Th1 and Th2 cells differ in their ability to produce chemokines, 
suggesting that Th1 and Th2 subsets differentially contribute to 
recruitment of cells into inflammatory foci.




PMID: 14500670
 

TITLE: Cysteine protease B of Leishmania mexicana inhibits host Th1 responses
and protective immunity.

AFFILIATION: Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, PA 19104, USA.

REFERENCE: J Immunol 2003 Oct 171(7):3711-7

C3H mice infected with Leishmania mexicana fail to develop a protective 
Th1 response, and are unable to cure. In this study, we show that L. 
mexicana cysteine proteases suppress the antileishmanial immune response
. Previous studies demonstrated that deletion of the entire multicopy 
cysteine protease B (CPB) gene array in L. mexicana is associated with 
decreased parasite virulence, potentially attributable to factors 
related to parasite fitness rather than to direct effects on the host 
immune response. We now show that C3H mice infected with the L. mexicana
 deletion mutant (Deltacpb) initially develop lesions that grow at rates
 comparable to those of wild-type L. mexicana-infected mice. However, in
 contrast to controls, Deltacpb-induced lesions heal with an 
accompanying Th1 immune response. Lesion resolution was Th1 dependent, 
as Deltacpb-infected IL-12p40(-/-) and STAT4(-/-) mice developed high 
parasite burdens and progressive disease. Moreover, when L. major was 
transfected with a cosmid expressing multiple L. mexicana CPB genes, 
this parasite induced a significantly lower IFN-gamma response compared 
with wild-type L. major. These data indicate that cysteine proteases of 
L. mexicana are critical in suppressing protective immune responses and 
that inhibition of CPB may prove to be a valuable immunomodulatory 
strategy for chronic forms of leishmaniasis.




PMID: 12811839
 

TITLE: Development of protective immunity against cutaneous leishmaniasis is
dependent on STAT1-mediated IFN signaling pathway.

AFFILIATION: Department of Microbiology, The Ohio State University, 484 West
12th Avenue, Columbus, OH 43210, USA.

REFERENCE: Eur J Immunol 2003 Jul 33(7):1799-805

Although STAT1-dependent signaling mediates biological functions of IFN-
alpha/beta and IFN-gamma, recent reports indicate that STAT1-independent
 IFN signaling also regulates expression of several genes. To determine 
the roles of STAT1-dependent and -independent IFN signaling in the 
regulation of immunity during cutaneous leishmaniasis, we studied the 
course of Leishmania major infection in resistant C57BL/6 mice lacking 
the STAT1 gene. While L. major-infected STAT1(+/+) mice resolved their 
lesions, STAT1(-/-) mice developed large lesions containing 
significantly more parasites. Moreover, the inability of STAT1(-/-) mice
 to control L. major infection was due to the lack of Th1 development 
associated with reduced production of IL-12, IFN-gamma and nitric oxide
. Although STAT1(-/-) mice produced more IL-4 and total IgE than STAT1
(+/+) mice later during infection, these differences were not 
significant. Nevertheless, at these time points lymph node cells from 
STAT1(-/-) mice produced significantly more IL-10. Finally, STAT1(-/-) 
mice were also susceptible to low dose L. major infection. Thesefindings
 demonstrate that STAT1-mediated IFN signaling is indispensable for the 
development of protective immunity against cutaneous L. major infection
. Moreover, they also suggest that the protective role of STAT1-mediated
 signaling is due to its ability to induce Th1 development during 
infection with this parasite.




PMID: 12682261
 

TITLE: Persistence of lesions in suppressor of cytokine signaling-1-deficient
mice infected with Leishmania major.

AFFILIATION: The Walter & Eliza Hall Institute of Medical Research and the
Cooperative Research Center for Cellular Growth Factors, Royal Melbourne
Hospital, Victoria, Australia.

REFERENCE: J Immunol 2003 Apr 170(8):4267-72

To investigate the role of the cytokine IFN-gamma and its negative 
regulator, the suppressor of cytokine signaling-1 (SOCS1) in the 
progression of cutaneous leishmaniasis, we infected mice lacking a 
single copy of the gene encoding SOCS1 (SOCS1(+/-)), mice lacking both 
copies of IFN-gamma (IFN-gamma(-/-)), or mice lacking copies of both 
SOCS1 and IFN-gamma (SOCS1(-/-) IFN-gamma(-/-)), with a moderate dose of
 10(3) or 10(4) of the most virulent stage of parasites, metacyclic 
promastigotes. Surprisingly, SOCS1(+/-) mice developed larger lesions 
than wild-type mice, although the parasite load in the draining lymph 
node was not significantly altered. These mice also developed apparently
 normal Th1 responses, as indicated by elevated levels of IFN-gamma and 
low levels of IL-4 and IL-10. The persistence of lesions and the 
enlargement of draining lymph nodes despite a normal Th1 response and 
control of parasitemia indicate that there may be a dissociation of the 
inflammatory pathology and clearance of parasites in SOCS1(+/-) mice. We
 also investigated the role of the related suppressor of cytokine 
signaling, SOCS2, which has been implicated in the development of Th1 
immunity. The progression of disease in SOCS2(-/-) mice did not differ 
from that in C57BL/6 control mice, suggesting that it is not involved in
 the host response to Leishmania major infection and supporting the 
specific role of SOCS1. These results suggest that SOCS1 plays an 
important role in the regulation of appropriate inflammatory responses 
during the resolution of L. major infection.




PMID: 12555666
 

TITLE: Control of New World cutaneous leishmaniasis is IL-12 independent but
STAT4 dependent.

AFFILIATION: Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, USA.

REFERENCE: Eur J Immunol 2002 Nov 32(11):3206-15

Leishmania mexicana, a New World protozoan parasite, induces small, 
chronic, but non-progressive lesions in C57BL/6 (B6) mice. In this study
 we investigated the role of IL-12, and subsequent Th1 factors, in 
controlling cutaneous L. mexicana infection. IL-12 treatment failed to 
promote disease resolution, suggesting that the inability of mice to 
heal is not related to a deficiency of endogenous IL-12 production. 
Surprisingly, L. mexicana-induced cutaneous lesions in wild-type and IL-
12p40-deficient mice were indistinguishable, with similar parasite 
burdens, immune responses, and lesion histopathology. In contrast, iNOS
, IFN-gamma, and STAT4-deficient mice developed progressive disease and 
uncontrolled parasite growth. These results differ dramatically from L. 
major infection, in which IL-12p40-deficient mice are highly susceptible
, with very rapid lesion growth, very large parasite burdens, and the 
development of a strong Th2 response. These data uncover the existence 
of an alternate IFN-gamma and iNOS pathway for control of Leishmania 
lesions, which is IL-12 independent, but which unexpectedly requires 
STAT4.




PMID: 12228277
 

TITLE: Identification of two distinct subpopulations of Leishmania
major-specific T helper 2 cells.

AFFILIATION: Department of Immunology, Division of Investigative Science,
Faculty of Medicine, Imperial College of Science, Technology and Medicine,
London, United Kingdom.

REFERENCE: Infect Immun 2002 Oct 70(10):5512-20

It is widely accepted that a strong Th2 response is responsible for 
nonhealing Leishmania major infections in BALB/c mice. This Th2 response
 has been thoroughly documented by measuring the levels of Th2 cytokines
 produced by CD4(+) T cells present in the lymphoid organs by enzyme-
linked immunosorbent assay and PCR. However, the cytokine profile of L. 
major-specific Th2 cells has never been determined. In this study, we 
used the recently described Th2 marker T1/ST2 to characterize Th2 cells 
during the course of nonhealing L. major infection. We analyzed the 
intracellular cytokine profile of CD4(+) T1/ST2(+) T cells and showed 
that they clearly displayed a Th2 phenotype, as they expressed 
interleukin 4 (IL-4), IL-10, and IL-5. In addition, we detected another 
population of Th2 cells among the CD4(+) T1/ST2(-) T cells that 
expressed IL-4 and IL-10 but excluded IL-5. In summary, we show here 
that two type 2 subpopulations are present in the lymphoid organs of L. 
major-infected BALB/c mice; Th2 cells from both subsets expressed IL-4 
and IL-10, but they could be distinguished by their expression of IL-5 
and T1/ST2.




PMID: 12653478
 

TITLE: The heat shock proteins, Hsp70 and Hsp83, of Leishmania infantum are
mitogens for mouse B cells.

AFFILIATION: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad
Autónoma de Madrid, Madrid 28049, Spain.

REFERENCE: Cell Stress Chaperones 2002 Oct 7(4):339-46

Extending earlier studies, this report demonstrates that Leishmania 
infantum heat shock proteins (Hsps), Hsp70 and Hsp83, expressed as 
recombinant proteins fused to the Escherichia coil maltose-binding 
protein (MBP), are potent mitogens for murine splenocytes. The response 
was not due to lipopolysaccharide (LPS) because the stimulatory activity
 of Hsp preparations was sensitive to boiling and trypsin treatments, 
whereas the corresponding activity of LPS was resistant to both 
treatments. It was found that in vitro incubation of spleen cells with 
the Leishmania Hsps leads to the expansion of CD220-bearing populations
, suggesting a direct effect of these proteins on B lymphocytes. In fact
, splenocytes from B cell-deficient mice did not proliferate in response
 to the Leishmania Hsps. In contrast, spleen cells from athymic nude 
mice were significantly stimulated by these recombinant proteins as an 
indication that the MBP-Hsp70 and MBP-Hsp83 recombinant proteins behave 
as T cell-independent mitogens of B cells. Furthermore, both proteins 
were able to induce proliferation on B cell populations purified from 
BALB/c spleen.




PMID: 12189207
 

TITLE: Dysregulated T helper cell differentiation in the absence of interferon
regulatory factor 4.

AFFILIATION: Institut für Medizinische Mikrobiologie, Pilgrimstein 2, 35037
Marburg, Germany.

REFERENCE: Proc Natl Acad Sci U S A 2002 Sep 99(18):11808-12

Certain IFN regulatory factor (IRF) transcription factors indirectly 
influence T helper (Th) cell differentiation by regulating the 
production of IL-12. Here, we show that IRF4 directly regulates Th cell 
differentiation in vitro and in vivo during murine leishmaniasis. In the
 absence of IRF4, IL-12-induced Th1 cell differentiation was compromised
, while IL-4 failed to induce Th2 cell differentiation. Instead, IL-4 
tended to induce Th1 cells, defined by production of IFN-gamma and TNF. 
Although early IL-4 signaling was normal in IRF4(-/-) Th cells, the 
protein GATA-3, a transcription factor critical for Th2 development, was
 not up-regulated following IL-4 treatment. Retroviral overexpression of
 GATA-3 rescued Th2 differentiation. Therefore, IRF4 deficiency 
manifests itself as severely dysregulated Th cell differentiation.















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