[Leish-l] Fwd: Articles found by RefScout 2006/01/26 2006/03

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REQUEST: [ leishmaniasis ]

(13 articles match this request)



PMID: 16328362
 

TITLE: Visceral leishmaniasis in a patient with Down syndrome.

AUTHORS: Claudia Colomba, Laura Saporito, Salvatore Giordano, Laura Infurnari,
Patrizia Ajovalasit, Lucina Titone

AFFILIATION: Istituto di Patologia Infettiva e Virologia, Università di
Palermo, Piazza Porta Montalto, 8-90134, Palermo, Italy,
claudia.colomba at libero.it.

REFERENCE: Eur J Pediatr 2006 Feb 165(2):140








PMID: 16318845
 

TITLE: Differential toxicity of antimonial compounds and their effects on
glutathione homeostasis in a human leukaemia monocyte cell line.

AUTHORS: Susan Wyllie, Alan H Fairlamb

AFFILIATION: Division of Biological Chemistry and Molecular Biology, Wellcome
Trust Biocentre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH
Scotland, UK.

REFERENCE: Biochem Pharmacol 2006 Jan 71(3):257-67

Trivalent antimonial compounds (Sb(III)), originally used in the 
treatment of leishmaniasis, are now being proposed as a novel therapy 
for acute promyelocytic leukaemia (APL). Here, we examine the effects of
 Sb(III) and pentavalent antimonial drugs (Sb(V)) on glutathione 
homeostasis, oxidative stress and apoptosis in the human leukaemia 
monocyte cell line, THP-1. Although growth of THP-1 macrophages is 
unaffected by Sb(V), macrophages are extremely sensitive to Sb(III). On 
exposure to Sb(III), intracellular free glutathione (GSH) levels in 
macrophages decrease linearly by 50% over 4h, associated with efflux of 
both GSH and accumulation of intracellular glutathione disulphide (GSSG
). Together these effects increase the redox potential of the GSSG/GSH 
couple from -282 to -225mV. Sb(III)-induced GSH efflux from THP-1 
macrophages is accompanied by the concomitant efflux of Sb(III) at a 
constant molar ratio of 3 (GSH) to 1 (Sb(III)), respectively. Sb(III) 
directly inhibits glutathione reductase activity in macrophages, 
significantly retarding the regeneration of GSH from GSSG, following 
diamide oxidation. Sb(III)-treated THP-1 macrophages go on to exhibit 
elevated levels of reactive oxygen species and show the early signs of 
apoptosis. The absence of these effects in Sb(V)-treated THP-1 cells 
suggests that macrophages do not efficiently reduce Sb(V) to Sb(III). 
Collectively, these findings suggest that Sb(III) seriously compromises 
thiol homeostasis in THP-1 macrophages and that this may be an early 
defining event in the mode of action of antimonials against leukaemia 
cells.




PMID: 16359155
 

TITLE: Nasal histoplasmosis in the acquired immunodeficiency syndrome.

AUTHORS: Felippe Felix, Geraldo Augusto Gomes, Patrícia Ciminelli Linhares
Pinto, Andréia Migueres Arruda, Marise da Penha Costa Marques, Shiro Tomita

AFFILIATION: Department of Otorhinolaryngology, University Hospital of the
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

REFERENCE: J Laryngol Otol 2006 Jan 120(1):67-9

Disseminated histoplasmosis is a disease with a high case-fatality rate
, especially in patients with the acquired immunodeficiency syndrome (
AIDS). The disease can occur in various sites, such as the lungs, eyes, 
oral cavity, larynx, nervous system, gastrointestinal tract and, more 
rarely, the nasal sinus region. It is a cosmopolitan mycosis with a high
 prevalence in Brazil. Nasal manifestation of the disease is rare, with 
only three cases reported in the literature, but it is part of the 
differential diagnosis for other granulomatous diseases, such as Wegener
's granulomatosis, tegumentary leishmaniasis and nasal lymphoma. The 
authors of this study present a literature review and report a case of 
nasal histoplasmosis in a patient with AIDS. No record of such an 
aggressive presentation has been reported previously in the literature.




PMID: 16243558
 

TITLE: Hemophagocytic syndrome associated with visceral leishmaniasis.

AUTHORS: Badreddine Kilani, Lamia Ammari, Fakher Kanoun, Taoufik Ben Chaabane,
Sami Abdellatif, Emna Chaker

AFFILIATION: Department of Infectious Diseases, Rabta Hospital, Tunis, Tunisia.

REFERENCE: Int J Infect Dis 2006 Jan 10(1):85-6




PMID: 16242844
 

TITLE: Canine visceral leishmaniasis: Comparison of in vitro leishmanicidal
activity of marbofloxacin, meglumine antimoniate and sodium stibogluconate.

AUTHORS: Ioannis Vouldoukis, Sandrine Rougier, Bernard Dugas, Paco Pino,
Dominique Mazier, Frédérique Woehrlé

AFFILIATION: INSERM U511, Immunobiologie Cellulaire et Moléculaire des
Infections Parasitaires, Université Paris VI, CHU-Pitié Salpétrière, 75013
Paris, France.

REFERENCE: Vet Parasitol 2006 Jan 135(2):137-46

The control of canine leishmaniasis largely depends on the success of 
treatment. Drugs currently available to treat this disease are toxic and
 partially effective. The curative effect of marbofloxacin, a third-
generation fluoroquinolone developed for veterinarian individual 
treatment, was evaluated in vitro in the presence of Leishmania infantum
 promastigotes and dog-monocyte-derived macrophages; meglumine 
antimoniate and sodium stibogluconate were used as comparative 
treatments. We observed that the killing of Leishmania promastigotes and
 intracellular amastigotes by marbofloxacin was dose-dependent. We 
demonstrated that successful treatment of canine infected macrophages 
for 48h was possible with 500mug/ml of marbofloxacin. Leishmanicidal 
activity acted through a TNF-alpha and nitric oxide pathway and 
correlated with the generation of nitric oxide (NO(2)) production by 
monocytes derived macrophages from infected (23+/-5muM) or healthy (21
+/-6muM) dogs, in comparison with NO(2) concentration in infected/non-
treated macrophages (<3muM, P<0.01). This significant induced 
parasiticidal effect correlated with extensive elimination of 
amastigotes by macrophages derived from infected (11+/-5) and healthy 
dogs (6+/-2), when compared to infected/non-treated macrophages (530+/-
105 and 472+/-86 amastigotes, respectively, P<0.01). Marbofloxacin 
was shown to be non-toxic at 500mug/ml in vitro and no cell apoptosis 
was observed. The molecule was able to induce a parasitic process after 
significant elimination of amastigotes in leishmania-infected dog 
macrophages. We propose that marbofloxacin, compared to standard 
chemotherapeutic agents (meglumine antimoniate and sodium stibogluconate
), could be an effective and pragmatic oral route alternative to treat 
canine leishmaniasis.








PMID: 16282534
 

TITLE: CD16+ monocytes in human cutaneous leishmaniasis: increased ex vivo
levels and correlation with clinical data.

AUTHORS: George Soares, Aldina Barral, Jackson M Costa, Manoel Barral-Netto,
Johan Van Weyenbergh

AFFILIATION: LIMI-CPqGM, Rua Waldemar Falcão 121, 40295-001 Salvador-BA,
Brazil. johan at cpqgm.fiocruz.br.

REFERENCE: J Leukoc Biol 2006 Jan 79(1):36-9

Peripheral blood CD16 (Fc receptor for immunoglobulin G III)-positive 
monocytes have been shown to expand in different pathological conditions
, such as cancer, asthma, sepsis, human immunodeficiency virus infection
, and AIDS progression, but data in leishmaniasis are lacking. We found 
that cutaneous leishmaniasis patients (n=15) displayed a significant 
increase in the percentage (3.5 vs. 10.1) as well as mean fluorescent 
intensity (13.5 vs. 29.2) of ex vivo CD16 expression in monocytes as 
compared with healthy controls. We observed a significant positive 
correlation between the percentage of ex vivo CD16(+) monocytes and 
lesion size (P=0.0052, r=0.75) or active transforming growth factor-beta
 plasma levels (P=0.0017, r=0.78). In addition, two patients with 
nonhealing lesions during a 3-year follow-up had high (9.1-19.4%) CD16 
levels at diagnosis. Our data suggest a deleterious role for CD16 in 
human leishmaniasis, as well as its possible use as a marker for disease
 severity and/or adverse disease outcome.




PMID: 16204283
 

TITLE: Renal involvement in a patient with visceral leishmaniasis.

AUTHORS: Georgios Efstratiadis, Evangelia Boura, Panagiotis Giamalis, Evdokia
Mandala, Maria Leontsini, Georgios Tsiaousis, Dimitrios Memmos

AFFILIATION: efstrati at med.auth.gr.

REFERENCE: Nephrol Dial Transplant 2006 Jan 21(1):235-6




PMID: 16371881
 

TITLE: Secondary hemophagocytic lymphohistiocytosis in Turkish children.

AUTHORS: Aytemiz Gurgey, Gulten Secmeer, Betul Tavil, Mehmet Ceyhan, Baris
Kuskonmaz, Bulent Cengiz, Hasan Ozen, Ates Kara, Mualla Cetin, Fatma Gumruk

AFFILIATION: Pediatric Hematology, Department of Pediatrics, Faculty of
Medicine, Hacettepe University, Ankara, Turkey. agurgey at hacettepe.edu.tr

REFERENCE: Pediatr Infect Dis J 2005 Dec 24(12):1116-7

Between January 1998 and January 2005, a total of 18 children 2 weeks-72
 months of age were diagnosed as having secondary hemophagocytic 
lymphohistiocytosis. The frequency of secondary hemophagocytic 
lymphohistiocytosis among total hospitalized patients during this period
 was 0.05% (18 of 34,250). Of the 18 patients, 8 (44.5%) had bacterial 
infections; cytomegalovirus and Epstein-Barr virus infections were 
present in 5 (28%) and 1 (5.5%), patient, respectively. Leishmaniasis 
was diagnosed in 2 patients (11%), and herpes simplex virus was 
diagnosed in 2 patients (11%). Six patients died during treatment, and 1
 patient was lost to follow-up. The survival rate was 61%.




PMID: 16054271
 

TITLE: Aluminium phosphate potentiates the efficacy of DNA vaccines against
Leishmania mexicana.

AUTHORS: Miguel Rosado-Vallado, Mirza Mut-Martin, Maria del Rosario
García-Miss, Eric Dumonteil

AFFILIATION: Laboratorio de Parasitología, Centro de Investigaciones
Regionales
Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán, Ave. Itzáes #490 x 59,
97000 Mérida, Yucatán, México.

REFERENCE: Vaccine 2005 Nov 23(46-47):5372-9

DNA vaccines have been able to induce partial protection against 
infection with Leishmania in mice, but it is still necessary to increase
 their efficacy. In the present study we evaluated aluminium phosphate 
as an adjuvant of different formulations and doses of DNA vaccines 
against L. mexicana in BALB/c mice. Aluminium phosphate had no effect on
 the humoral response induced by a high dose (100 microg) DNA vaccine, 
but slightly increased the cellular response and the protection against 
infection. It also allowed a non-immunoprotective low dose (20 microg) 
DNA vaccine encoding L. mexicana GP63 and Leishmania donovani NH36 to 
become protective. Aluminium phosphate may thus be an effective, low 
cost and safe adjuvant for DNA vaccines, and the vaccine formulation 
described here may be an excellent candidate for further vaccine 
development against Leishmania.




PMID: 16149989
 

TITLE: Co-infected C57BL/6 mice mount appropriately polarized and
compartmentalized cytokine responses to Litomosoides sigmodontis and Leishmania
major but disease progression is altered.

AUTHORS: T J Lamb, A L Graham, L Le Goff, J E Allen

AFFILIATION: Institutes of Evolution, Immunology, & Infection Research, School
of Biological Sciences, University of Edinburgh, UK.

REFERENCE: Parasite Immunol 2005 Sep 27(9):317-24

This study examines the capacity of the mammalian host to fully 
compartmentalize the response to infection with type 1 vs. type 2 
inducing organisms that infect different sites in the body. For this 
purpose, C57BL/6 mice were infected with the rodent filarial nematode 
Litomosoides sigmodontis followed by footpad infection with the 
protozoan parasite Leishmania major. In this host, nematode infection is
 established in the thoracic cavity but no microfilariae circulate in 
the bloodstream. We utilized quantitative ELISPOT analysis of IL-4 and 
IFN-gamma producing cells to assess cytokine bias and response magnitude
 in the lymph nodes draining the sites of infection as well as more 
systemic responses in the spleen and serum. Contrary to other systems 
where co-infection has a major impact on bias, cytokine ratios were 
unaltered in either local lymph node. The most notable effect of co-
infection was an unexpected increase in the magnitude of the IFN-gamma 
response to L. major in mice previously infected with L. sigmodontis. 
Further, lesion development was significantly delayed in these mice. 
Thus, despite the ability of the immune system to appropriately 
compartmentalize the immune response, interactions between responses at 
distinct infection sites can alter disease progression.




********************************************************************************************************************

 The following references are revised files and are brought to you in
accordance
to license agreement with the NLM.

********************************************************************************************************************






PMID: 15895170
 

TITLE: Retrospective study of 151 patients with cutaneous leishmaniasis treated
with meglumine antimoniate.

AUTHORS: Armando de Oliveira Schubach, Keyla B Feldman Marzochi, João Soares
Moreira, Tânia Maria Pacheco Schubach, Marcelo Lodi Araújo, Antônio Carlos
Francesconi do Vale, Sonia Regina Lambert Passos, Mauro Célio de Almeida
Marzochi

AFFILIATION: Centro de Referências em Leishmanioses, Instituto de Pesquisa
Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
armando at ipec.fiocruz.br

REFERENCE: Rev Soc Bras Med Trop 2005 May-Jun 38(3):213-7

We retrospectively analyzed a series of 151 cases of cutaneous 
leishmaniasis treated between 1967 and 1982. One-hundred-and-thirty-nine
 (92%) patients presented with active lesions and were treated with 
daily doses of meglumine antimoniate: 81 adults received a 5-ml vial IM 
and 58 children received 1 to 5 ml. Forty-five (32.4%) patients 
underwent continuous treatment with meglumine antimoniate for 25 to 116 
days without rest intervals, and 94 (67.6%) intermittent treatment with 
2 to 5 series of meglumine antimoniate. Intermittent series could 
include schedules of daily IM applications for 10 to 25 days each and 
intervals varying from 10 to 60 days. Antimony dose was calculated for 
66 (47.5%) patients and ranged from 3.9 to 28.7 Sb5+/kg/day. Of these, 
35 patients received > or =10 mg and 31 patients < 10 mg Sb5+/kg/day
. Median time of healing was longer for lesions on the legs and feet -- 
67.5 days versus 48.7 days (p < 0.001) for other sites. However, 
there were no significant differences in the median time of healing 
between adults and children, intermittent and continuous regimens or 
high and low antimony doses. Fifty-one patients were reassessed 5 to 14 
years after treatment and showed no evidence of disease. These results 
support further investigation (clinical trials) on treatment using low 
doses of antimony.




PMID: 12612734
 

TITLE: [Anti-live Leishmania (Viannia) braziliensis promastigote antibodies,
detected by flow cytometry, to identify active infection in american cutaneous
leishmaniasis]

AUTHORS: Roberta Dias Rodrigues Rocha, Célia Maria Ferreira Gontijo, Silvana
Maria Elói-Santos, Andréa Teixeira Carvalho, Rodrigo Corrêa-Oliveira, Marcos
José Marques, Odair Genaro, Wilson Mayrink, Olindo Assis Martins-Filho

AFFILIATION: Laboratório de Doença de Changas do Centro de Pesquisas René
Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil.

REFERENCE: Rev Soc Bras Med Trop 2002 Nov-Dec 35(6):551-62

In the current study we described initial standardization steps of a new
 methodology to detect anti-live Leishmania (Viannia) braziliensis 
promastigote antibodies by flow cytometry, followed by analysis of its 
applicability to clinical studies. We have studied 39 individuals with 
positive conventional serology to leishmaniasis, classified according to
 the absence/presence of cutaneous lesions (L- and L+). The results were
 expressed as percentage of positive fluorescent parasites (PPFP). Data 
analysis at dilution of 1:1,024, allowed the distinction of 95% of L+ 
patients as a group of high reactivity (PPFP>50%) and 72% of L- 
individuals as a group of low reactivity (PPFP<50%). The analysis of 
immunofluorescence assay titers did not show any relationship with the 
absence/presence of lesion. Together, our data support the applicability
 of flow cytometry to identify cases of active infection, which has not 
been possible through conventional serological reactions.




PMID: 9739094
 

TITLE: The crystal structure of the Leishmania major surface proteinase
leishmanolysin (gp63).

AUTHORS: E Schlagenhauf, R Etges, P Metcalf

AFFILIATION: EMBL Heidelberg, Biological Structures and Biocomputing Programme,
Germany.

REFERENCE: Structure 1998 Aug 6(8):1035-46

BACKGROUND: Despite their medical importance, there is little available 
structural information for the surface antigens of infectious protozoa. 
Diseases caused by the protozoan parasite Leishmania are common in many 
developing countries. Human infection occurs during the bite of infected
 sandfilies, when Leishmania promastigote cells from the insect gut 
enter the bloodstream. Promastigotes in the blood parasitize macrophages
, often causing serious disease. Leishmanolysin is the predominant 
protein surface antigen of promastigotes, and is assumed to have a key 
role during infection. Leishmanolysin is a membrane-bound zinc 
proteinase, active in situ. Similar molecules exist in other 
trypanomastid protozoa. RESULTS: Two crystal forms of leishmanolysin 
were obtained from protein purified from promastigote membranes. A 
single lead derivative in both crystal forms was used to solve the 
structure. The structure reveals three domains, two of which have novel 
folds. The N-terminal domain has a similar structure to the catalytic 
modules of zinc proteinases. The structure clearly shows that 
leishmanolysin is a member of the metzincin class of zinc proteinases. 
CONCLUSIONS: The unexpected metzincin features of the leishmanolysin 
structure suggest that the metzincin fold may be more widespread than 
indicated by sequence homologies amongst existing metzincin zinc 
proteinases. The similarity of the active-site structure to previously 
well characterized metzincin class zinc proteinases should aid the 
development of specific inhibitors. These inhibitors might be used to 
determine the function of leishmanolysin in the insect and during 
mammalian infection, and may aid the development of drugs for human 
leishmaniasis.




REQUEST: [ leishmania ]

(10 articles match this request. 3 articles matching other requests removed)



PMID: 16315289
 

TITLE: Large-scale survey for potentially targetable indels in bacterial and
protozoan proteins.

AUTHORS: Artem Cherkasov, Shang-Jung Lee, Devki Nandan, Neil E Reiner

AFFILIATION: Department of Medicine (Division of Infectious Diseases),
University of British Columbia, Faculties of Medicine and Science, and
Vancouver Coastal Health Research Institute (VCHRI), Vancouver, British
Columbia, Canada.

REFERENCE: Proteins 2006 Feb 62(2):371-80

Our previous results demonstrated that some essential, housekeeping 
proteins from pathogenic microorganisms may contain sizable insertions-
deletions in their sequences (compared to close human homologs) that can
 be responsible for unexpected virulence properties. For example, we 
found that indel-bearing elongation factor-1alpha from several 
pathogenic protozoa can activate a human tyrosine phosphatase SHP-1 
leading to deactivation of macrophages. On the one hand, these findings 
allowed development of a strategy for targeting some indel-containing 
pathogen proteins that have similar human counterparts. On the other 
hand, the results raised numerous questions regarding the nature and 
implications of sequence indels in pathogen proteins. In the present 
study, we conducted a large-scale survey of indels in proteins from 136 
bacterial and protozoan genomes. It has been established that sizable 
insertions and deletions occur in approximately 5-10% of bacterial 
proteins with close human homologs, while proteins from the protozoan 
pathogens such as Trypanosoma cruzi, Plasmodium falciparum, and 
Leishmania donovani exhibit elevated indel content that can reach up to 
25%. The finding suggested that the occurrence of sequence indels may be
 involved in the evolution of pathogenic mechanisms in these protozoa. 
Proteins 2006. (c) 2005 Wiley-Liss, Inc.




PMID: 16377672
 

TITLE: Resistance of Leishmania donovani to Sodium Stibogluconate Is Related to
the Expression of Host and Parasite {gamma}-Glutamylcysteine Synthetase.

AUTHORS: K C Carter, S Hutchison, F L Henriquez, D Légaré, M Ouellette, C W
Roberts, A B Mullen

AFFILIATION: Department of Immunology, SIBS, University of Strathclyde, 31
Taylor Street, Glasgow G4 0NR, United Kingdom. k.carter at strath.ac.uk.

REFERENCE: Antimicrob Agents Chemother 2006 Jan 50(1):88-95

Sequencing studies showed that the gamma-glutamylcysteine synthetase (
gamma-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant
 (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were 
identical, indicating that SSG resistance was related to quantitative 
differences in gamma-GCS expression rather than gene interstrain 
polymorphisms. In vitro infection of murine macrophages with the SSG-R 
strain, but not the SSG-S strain, down regulated expression of host 
gamma-GCS, which would result in a reduction in intramacrophage 
glutathione (GSH) levels and promote an oxidative intramacrophage 
environment. This would inhibit, or minimize, the reduction of SSG 
pentavalent antimony to its more toxic trivalent form. Macrophage 
studies showed that the SSG-R strain expressed higher levels of gamma-
GCS compared to the SSG-S strain, which would result in higher GSH 
levels, giving increased protection against oxidative stress and 
facilitating SSG efflux. However a similar differential effect on host 
and parasite gamma-GCS expression was not obtained when using tissues 
from infected mice. In this case gamma-GCS expression was organ and 
strain dependent for both the host and the parasite, indicating that 
environmental conditions have a profound effect on gamma-GCS expression
. Consistent with the proposed mechanism from in vitro studies, 
increasing tissue GSH levels in the presence of SSG by cotreatment of L
. donovani-infected mice with SSG solution and GSH incorporated into 
nonionic surfactant vesicles was more effective in reducing liver, 
spleen, and bone marrow parasite burdens than monotherapy with SSG. 
Together, these results indicate that SSG resistance is associated with 
manipulation of both host and parasite GSH levels by L. donovani.








PMID: 16213661
 

TITLE: Immune response to Leishmania infantum in healthy horses in Spain.

AUTHORS: Hugo Fernández-Bellon, Laia Solano-Gallego, Mar Bardagí, Jordi
Alberola, Antonio Ramis, Lluis Ferrer

AFFILIATION: Departament de Medicina i Cirurgia Animals, Facultat de VeterinÃ
ria, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.

REFERENCE: Vet Parasitol 2006 Jan 135(2):181-5

Leishmania infantum infection has recently been described in horses in 
Europe. We report the results of a study on the immune response to L. 
infantum in horses living in an area endemic for leishmaniosis in NE 
Spain. Two ELISAs using protein A and anti-horse IgG conjugates were 
adapted to measure specific antibodies to L. infantum in horse sera. A 
lymphocyte proliferation assay (LPA) of peripheral blood mononuclear 
cells to L. infantum antigen was also performed to detect specific 
cellular immune response to Leishmania. Anti-L. infantum antibodies were
 detected in the serum of 16 of the horses studied (n=112) using the 
protein A assay but not in the assay using the anti-horse IgG conjugate
. Specific lymphocyte proliferation was observed in 20 out of 55 horses
. This study shows that horses in the area studied mount specific immune
 responses to L. infantum, and must therefore be considered among the 
species exposed to the parasite in this region. The infrequency of 
leishmaniosis in horses suggests that the immune response in this 
species is effective in controlling the infection.




PMID: 16174567
 

TITLE: An intrinsic 5'-deoxyribose-5-phosphate lyase activity in DNA polymerase
beta from Leishmania infantum supports a role in DNA repair.

AUTHORS: Ana Alonso, Gloria Terrados, Angel J Picher, Rafael Giraldo, Luis
Blanco, Vicente Larraga

AFFILIATION: Centro de Investigaciones Biológicas, CSIC, c/Ramiro de Maeztu 9,
28040 Madrid, Spain.

REFERENCE: DNA Repair (Amst) 2006 Jan 5(1):89-101

Leishmania infantum is a parasitic protozoan which infects humans. This 
paper reports the expression in Escherichia coli and purification of the
 L. infantum gene product (), as well as its characterization as a DNA 
polymerase beta (Polbeta)-like, template-dependent DNA repair enzyme, 
with a metal preference for Mn(2+) over Mg(2+). As is the case with 
mammalian Polbeta and DNA polymerase lambda (Pollambda), L. infantum DNA
 polymerase beta (Li Polbeta) prefers gapped-DNA substrates having a 5'-
phosphate end, in agreement with its role in DNA repair reactions. 
Purified Li Polbeta also displayed a 5'-deoxyribose-5-phosphate (dRP) 
lyase activity, consistent with a beta-elimination mechanism. The 
concerted action of dRP lyase and DNA polymerization activities of Li 
Polbeta on a uracil-containing DNA suggests its participation in "
single-nucleotide" base excision repair (BER). Analysis of Li 
Polbeta DNA polymerization activity at different stages of the L. 
infantum infective cycle supports a role for Li Polbeta in nuclear DNA 
repair after the oxidative damage occurring inside the macrophage.




PMID: 16310148
 

TITLE: Treatment options for visceral leishmaniasis: a systematic review of
clinical studies done in India, 1980-2004.

AUTHORS: Piero L Olliaro, Philippe J Guerin, Sibylle Gerstl, Astrid Aga
Haaskjold, John-Arne Rottingen, Shyam Sundar

AFFILIATION: UNICEF/UNDP/World Bank/WHO Special Programme on Research and
Training in Tropical Diseases, WHO, Geneva, Switzerland. olliarop at who.int

REFERENCE: Lancet Infect Dis 2005 Dec 5(12):763-74

The state of Bihar in India carries the largest share of the world's 
burden of antimony-resistant visceral leishmaniasis. We analysed 
clinical studies done in Bihar with different treatments between 1980 
and 2004. Overall, 53 studies were included (all but one published), of 
which 15 were comparative (randomised, quasi-randomised, or non-
randomised), 23 dose-finding, and 15 non-comparative. Data from 
comparative studies were pooled when appropriate for meta-analysis. 
Overall, these studies enrolled 7263 patients in 123 treatment arms. 
Adequacy of methods used to do the studies and report on them varied. 
Unresponsiveness to antimony has developed steadily in the past to such 
an extent that antimony must now be replaced, despite attempts to stop 
its progression by increasing dose and duration of therapy. The classic 
second-line treatments are unsuited: pentamidine is toxic and its 
efficacy has also declined, and amphotericin B deoxycholate is effective

 but requires hospitalisation for long periods and toxicity is common. 
Liposomal amphotericin B is very effective and safe but currently 
unaffordable because of its high price. Miltefosine-the first oral drug 
for visceral leishmaniasis-is now registered and marketed in India and 
is effective, but should be used under supervision to prevent misuse. 
Paromomycin (or aminosidine) is effective and safe, and although not yet
 available, a regulatory submission is due soon. To preserve the limited
 armamentarium of drugs to treat visceral leishmaniasis, drugs should 
not be deployed unprotected; combinations can make drugs last longer, 
improve treatment, and reduce costs to households and health systems. 
India, Bangladesh, and Nepal agreed recently to undertake measures 
towards the elimination of visceral leishmaniasis. The lessons learnt in
 Bihar could help inform policy decisions both regionally and elsewhere.




********************************************************************************************************************

 The following references are revised files and are brought to you in
accordance
to license agreement with the NLM.

********************************************************************************************************************


PMID: 10801498
 

TITLE: A potential target enzyme for trypanocidal drugs revealed by the crystal
structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania
mexicana.

AUTHORS: S Suresh, S Turley, F R Opperdoes, P A Michels, W G Hol

AFFILIATION: Department of Biological Structure, Biomolecular Structure Center,
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195,
USA.

REFERENCE: Structure 2000 May 8(5):541-52

BACKGROUND: NAD-dependent glycerol-3-phosphate dehydrogenase (GPDH) 
catalyzes the interconversion of dihydroxyacetone phosphate and L-
glycerol-3-phosphate. Although the enzyme has been characterized and 
cloned from a number of sources, until now no three-dimensional 
structure has been determined for this enzyme. Although the utility of 
this enzyme as a drug target against Leishmania mexicana is yet to be 
established, the critical role played by GPDH in the long slender 
bloodstream form of the related kinetoplastid Trypanosoma brucei makes 
it a viable drug target against sleeping sickness. RESULTS: The 1.75 A 
crystal structure of apo GPDH from L. mexicana was determined by 
multiwavelength anomalous diffraction (MAD) techniques, and used to 
solve the 2.8 A holo structure in complex with NADH. Each 39 kDa subunit
 of the dimeric enzyme contains a 189-residue N-terminal NAD-binding 
domain and a 156-residue C-terminal substrate-binding domain. 
Significant parts of both domains share structural similarity with plant
 acetohydroxyacid isomeroreductase. The discovery of extra, fatty-acid 
like, density buried inside the C-terminal domain indicates a possible 
post-translational modification with an associated biological function. 
CONCLUSIONS: The crystal structure of GPDH from L. mexicana is the first
 structure of this enzyme from any source and, in view of the sequence 
identity of 63%, serves as a valid model for the T. brucei enzyme. The 
differences between the human and trypanosomal enzymes are extensive, 
with only 29% sequence identity between the parasite and host enzyme, 
and support the feasibility of exploiting the NADH-binding site to 
develop selective inhibitors against trypanosomal GPDH. The structure 
also offers a plausible explanation for the observed inhibition of the T
. brucei enzyme by melarsen oxide, the active form of the trypanocidal 
drugs melarsoprol and cymelarsan.




PMID: 10801489
 

TITLE: The crystal structure and active site location of isocitrate lyase from
the fungus Aspergillus nidulans.

AUTHORS: K Britton, S Langridge, P J Baker, K Weeradechapon, S E Sedelnikova, J
R De Lucas, D W Rice, G Turner

AFFILIATION: Department of Molecular Biology and Biotechnology, Krebs Institute
for Biomolecular Research, The University of Sheffield, Sheffield, S10 2TN,
UK.

REFERENCE: Structure 2000 Apr 8(4):349-62

BACKGROUND: Isocitrate lyase catalyses the first committed step of the 
carbon-conserving glyoxylate bypass, the Mg(2+)-dependent reversible 
cleavage of isocitrate into succinate and glyoxylate. This metabolic 
pathway is an inviting target for the control of a number of diseases, 
because the enzymes involved in this cycle have been identified in many 
pathogens including Mycobacterium leprae and Leishmania. RESULTS: As 
part of a programme of rational drug design the structure of the 
tetrameric Aspergillus nidulans isocitrate lyase and its complex with 
glyoxylate and a divalent cation have been solved to 2.8 A resolution 
using X-ray diffraction. Each subunit comprises two domains, one of 
which adopts a folding pattern highly reminiscent of the triose 
phosphate isomerase (TIM) barrel. A 'knot' between subunits observed in 
the three-dimensional structure, involving residues towards the C 
terminus, implies that tetramer assembly involves considerable 
flexibility in this part of the protein. CONCLUSIONS: Difference Fourier
 analysis together with the pattern of sequence conservation has led to 
the identification of both the glyoxylate and metal binding sites and 
implicates the C-terminal end of the TIM barrel as the active site, 
which is consistent with studies of other enzymes with this fold. Two 
disordered regions of the polypeptide chain lie close to the active site
, one of which includes a critical cysteine residue suggesting that 
conformational rearrangements are essential for catalysis. Structural 
similarities between isocitrate lyase and both PEP mutase and enzymes 
belonging to the enolase superfamily suggest possible relationships in 
aspects of the mechanism.




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