The risk for reintroduction of some exotic vector-borne diseases in Europe has become a hot topic, while the reality of others is neglected at the public health policy level. Leishmaniasis is endemic in all southern countries of Europe, with ≈700 autochthonous human cases reported each year (3,950 if Turkey is included). Asymptomatic cases have been estimated at 30–100/1 symptomatic case, and leishmaniasis has up to 25% seroprevalence in domestic dogs. Even though leishmaniasis is essentially associated with Leishmania infantum and visceral leishmaniasis, new species, such as L. donovani and L. tropica, might colonize European sand fl y vectors. Drug-resistant L. infantum strains might be exported outside Europe through dogs. Despite this possibility, no coordinated surveillance of the disease exists at the European level. In this review of leishmaniasis importance in Europe, we would like to bridge the gap between research and surveillance and control.

Spread of Vector-borne Diseases and Neglect of Leishmaniasis, Europe

It is important to realize that leishmaniasis guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA and ASTMH consider adherence to these guidelines to be voluntary, with the ultimate determinations regarding their application to be made by the physician in the light of each patient's individual circumstances.

Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)

Leishmaniasis is a cluster of diseases caused by protozoa in the genus Leishmania. There are three basic clinical forms: cutaneous, mucocutaneous, and visceral leishmaniasis. The present review focuses on the diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Characteristics of both the human host and the parasite species influence the clinical disease manifestations that range from asymptomatic exposure, to self-healing skin ulcers, to life-threatening widespread destructive ulcerations. Whether through medical treatment or through spontaneous resolution, skin ulcerations generally result in disfiguring scars with significant social and economic impact. Tests to confirm the diagnosis should be performed on patients who have recently visited endemic areas and have skin or mucosal manifestations consistent with leishmaniasis. Treatment depends on the species of Leishmania and the risk of widespread or disfiguring disease. Because of increasing trends in global travel, educating health care providers to recognize and treat leishmaniasis in both endemic and non-endemic countries is imperative.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1529-8019.2009.01272.x

Cutaneous and mucocutaneous leishmaniasis.

/pdf/diagnosis-and-treatment-of-leishmaniasis-clinical-practice-nlblkirt8h.pdf

Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)*

First generation leishmaniasis vaccines : A review of field efficacy trials

Background 
Recent circumstantial evidence suggests that an increasing number of Iranian patients with cutaneous leishmaniasis are unresponsive to meglumine antimoniate (Glucantime), the first line of treatment in Iran. This study was designed to determine whether the clinical responses (healing, or non-healing) were correlated with the susceptibility of Leishmania parasites to Glucantime. 
Methods and Findings 
In vitro susceptibility testing was first performed on 185 isolated parasites in the intracellular mouse peritoneal macrophage model. A strong correlation between the clinical outcome and the in vitro effective concentration 50% (EC50) values was observed. Parasites derived from patients with non-healing lesions had EC50 values at least 4-fold higher than parasites derived from lesions of healing patients. A selection of these strains was typed at the molecular level by pulsed-field gels and by sequencing the pteridine reductase 1 (PTR1) gene. These techniques indicated that 28 out of 31 selected strains were Leishmania tropica and that three were Leishmania major. The L. major isolates were part of a distinct pulsed-field group, and the L. tropica isolates could be classified in three related additional pulsed-field groups. For each pulsed-field karyotype, we selected sensitive and resistant parasites in which we transfected the firefly luciferase marker to assess further the in vitro susceptibility of field isolates in the monocyte cell line THP1. These determinations confirmed unequivocally that patients with non-healing lesions were infected with L. tropica parasites resistant to Glucantime. Additional characterization of the resistant isolates showed that resistance is stable and can be reversed by buthionine sulfoximine, an inhibitor of glutathione biosynthesis. 
Conclusions 
To the authors' knowledge, this is the first report of proven resistant parasites contributing to treatment failure for cutaneous leishmaniasis and shows that primary Glucantime-resistant L. tropica field isolates are now frequent in Iran.

/pdf/unresponsiveness-to-glucantime-treatment-in-iranian-2jd1wysz0s.pdf

Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites.

Cutaneous leishmaniasis (CL) is a major health problem in endemic areas of Iran. The pentavalent antimony (SbV) based drug Glucantime is the first line of treatment for CL in Iran, but recently SbV-resistant Leishmania tropica isolates derived from unresponsive patients were reported. We show in this study that these resistant parasites are cross-resistant to the other SbV-containing drug Pentostam and at least for one isolate also to amphotericin B. However, these resistant isolates were shown to be sensitive to miltefosine and paromomycin. The latter two drugs could thus be useful alternatives for the treatment of leishmaniasis in Iran even for SbV-resistant isolates.

Glucantime-resistant Leishmania tropica isolated from Iranian patients with cutaneous leishmaniasis are sensitive to alternative antileishmania drugs

The emergence of therapy-related acute myeloid leukemia (t-AML) has been associated with DNA topoisomerase II (TOP2)–targeted drug treatments and chromosomal translocations frequently involving the MLL, or ALL-1, gene. Two distinct mechanisms have been implicated as potential triggers of t-AML translocations: TOP2-mediated DNA cleavage and apoptotic higher-order chromatin fragmentation. Assessment of the role of TOP2 in this process has been hampered by a lack of techniques allowing in vivo mapping of TOP2-mediated DNA cleavage at nucleotide resolution in single-copy genes. A novel method, extension ligation-mediated polymerase chain reaction (ELMPCR), was used here for mapping topoisomerase-mediated DNA strand breaks and apoptotic DNA cleavage across a translocation-prone region of MLL in human cells. We report the first genomic map integrating translocation breakpoints and topoisomerase I, TOP2, and apoptotic DNA cleavage sites at nucleotide resolution across an MLL region harboring a t-AML translocation hotspot. This hotspot is flanked by a TOP2 cleavage site and is localized at one extremity of a minor apoptotic cleavage region, where multiple single- and double-strand breaks were induced by caspase-activated apoptotic nucleases. This cleavage pattern was in sharp contrast to that observed ∼200 bp downstream in the exon 12 region, which displayed much stronger apoptotic cleavage but where no double-strand breaks were detected and no t-AML–associated breakpoints were reported. The localization and remarkable clustering of the t-AML breakpoints cannot be explained simply by the DNA cleavage patterns but might result from potential interactions between TOP2 poisoning, apoptotic DNA cleavage, and DNA repair attempts at specific sites of higher-order chromatin structure in apoptosis-evading cells. ELMPCR provides a new tool for investigating the role of DNA topoisomerases in fundamental genetic processes and translocations associated with cancer treatments involving topoisomerase-targeted drugs.

Patrick Boucher

Papers

Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites.

Glucantime-resistant Leishmania tropica isolated from Iranian patients with cutaneous leishmaniasis are sensitive to alternative antileishmania drugs

Nucleotide-Resolution Mapping of Topoisomerase-Mediated and Apoptotic DNA Strand Scissions at or near an MLL Translocation Hotspot