Highlights • Leishmania infections in HIV positive patients have increasingly been reported in last 25 years, mostly from Mediterranean region. • Both infectious agents cause host immune suppression ...in a synergistic manner leading to faster disease progression and atypical manifestations. • So far at least 102 cases of HIV-Leishmania co-infections have been reported from India with different clinical manifestations (VL 89; CL 10; PKML 1; undefined 2), but after HAART therapy number of new cases has come down. • In HIV-VL co-infected patients, though immunological methods are most commonly used with high diagnostic accuracy, their analytical sensitivity remains low and end point antibody titers are several folds lower in HIV infected VL patients. • Molecular methods have been found most promising diagnostic tool for both visceral and tegumentary leishmaniasis with several advantages, such as extremely high sensitivity, rapidity and the ability to work with a broad range of clinical specimens and these can predict therapeutic efficacy of specific drugs, disease outcome, relapses and species, strain or genotype identification.
Miltefosine unresponsive and relapse cases of visceral leishmaniasis (VL) are increasingly being reported. However, there has been no laboratory confirmed reports of miltefosine resistance in VL. ...Here, we report two laboratory confirmed cases of VL from India.
Two patients with VL were referred to us with suspected VL. The first patient was a native of the VL endemic state of Bihar, but residing in Delhi, a VL non-endemic area. He was treated with broad-spectrum antibiotics and antipyretics but was unresponsive to treatment. The second patient was from Jharkhand state in eastern India (adjoining Bihar), another endemic state for VL. He was refractory to anti-leishmanial treatment, which included administration of miltefosine. Following investigation, both patients were serologically positive for VL, and blood buffy coat from both patients grew Leishmania donovani. The isolates derived from both cases were characterized for their drug susceptibility, genetically characterised, and SNPs typed for LdMT and LdROS gene expression. Both patients were successfully treated with amphotericin B.
The in vitro drug susceptibility assays carried out on both isolates showed good IC
values to amphotericin B (0.1 ± 0.0004 μg/ml and 0.07 ± 0.0019 μg/ml). One isolate was refractory to Sb
with an IC
of > 200 μM while the second isolate was sensitive to Sb
with an IC
of 36.70 ± 3.2 μM. However, in both the isolates, IC
against miltefosine was more than 10-fold higher (> 100 μM) than the standard strain DD8 (6.8 ± 0.1181 μM). Furthermore, genetic analyses demonstrated single nucleotide polymorphisms (SNPs) (
Tyr↔Phe and
Phe↔Tyr) in the LdMT gene of the parasites.
Here, we document two laboratory confirmed cases of miltefosine resistant VL from India. Our finding highlights the urgent need to establish control measures to prevent the spread of these strains. We also propose that LdMT gene mutation analysis could be used as a molecular marker of miltefosine resistance in L. donovani.
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.
Leishmaniasis is a parasitic disease caused by 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. Nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. The pentavalent antimony compounds have remained mainstay for nearly 75 years. Pentavalent antimony is a prodrug that is reduced by glutathione to active trivalent species catalyzed by thiol-dependent-reductase. However, emergence of resistance led to the use of other compounds -amphotericin B, pentamidine, paromomycin, allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis. Presently, it is the only drug with highest cure rate. It acts on membrane sterols resulting in parasite cell lysis. Its lipid formulations have been developed to minimize side effects. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), edelfosine (ET-18-OCH3) and ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.
Scarcely understood defects lead to asthenozoospermia, which results in poor fertility outcomes. Incomplete knowledge of these defects hinders the development of new therapies and reliance on ...interventional therapies, such as in vitro fertilization, increases. Sperm cells, being transcriptionally and translationally silent, necessitate the proteomic approach to study the sperm function. We have performed a differential proteomics analysis of human sperm and seminal plasma and identified and quantified 667 proteins in sperm and 429 proteins in seminal plasma data set, which were used for further analysis. Statistical and mathematical analysis combined with pathway analysis and self-organizing maps clustering and correlation was performed on the data set.
It was found that sperm proteomic signature combined with statistical analysis as opposed to the seminal plasma proteomic signature can differentiate the normozoospermic versus the asthenozoospermic sperm samples. This is despite the results that some of the seminal plasma proteins have big fold changes among classes but they fall short of statistical significance. S-Plot of the sperm proteomic data set generated some high confidence targets, which might be implicated in sperm motility pathways. These proteins also had the area under the curve value of 0.9 or 1 in ROC curve analysis.
Various pathways were either enriched in these proteomic data sets by pathway analysis or they were searched by their constituent proteins. Some of these pathways were axoneme activation and focal adhesion assembly, glycolysis, gluconeogenesis, cellular response to stress and nucleosome assembly among others. The mass spectrometric data is available via ProteomeXchange with identifier PXD004098.
Genotype MTBDRsl Version 1 (V1.0) was recommended as an initial test for rapid detection of pre-extensively drug resistant (pre-XDR) and extensively drug resistant tuberculosis (XDR-TB). However, in ...recent years a number of novel mutations are identified that confer resistance. Thus, Genotype MTBDRsl V2.0 was endorsed by WHO. Though, Genotype MTBDRsl V2.0 has been rolled out in national TB programme in 2018, there is dearth of data from India on its performance for second line drug susceptibility testing (DST). For this, performance of new version was evaluated on 113 MDR-TB isolates. The results showed that 39 (34.5%) of these isolates were resistant to FQ and 7 (6.2%) were XDR by Genotype MTBDRsl V2.0. Amongst the FQ resistant isolates most prevalent mutation was ΔWT3-D94G (17; 38.6%) and N538D (12; 85.7%). Among the AG/CP and KAN resistant isolates most common mutation in the rrs region was ΔWT1-A1401G (5; 71.4%) and C-14T (2; 28.5%) in eis gene. Second line Bactec MGIT-960 detected 40 (35.4%) isolates as resistant to FQ and 6 (5.3%) as XDR isolates, whereas Genotype MTBDRsl V1.0 also detected 39 (34.5%) as resistant to FQ but missed 2 isolates in correctly identifying as XDR (5; 4.4%). Thus, concordance of second line Bactec MGIT-960 with Genotype MTBDRsl V2.0 was similar (100%) for FQ detection but it has improvised the diagnostic sensitivity for correctly identifying XDR isolates. Nevertheless, the cost of Genotype MTBDRsl V2.0 remains an issue for screening of second line drug (SLDs) resistance from countries with high burden of MDR-TB.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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