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1.
PLoS One ; 15(12): e0243392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370295

RESUMO

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 µg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 µg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.


Assuntos
Antiprotozoários/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Leishmania guyanensis/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Alcaloides/farmacologia , Animais , Antiprotozoários/química , Cricetinae , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Leishmania guyanensis/patogenicidade , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Óxido Nítrico/genética , Folhas de Planta/química , Quinolinas/química , Quinolonas/farmacologia , Rutaceae/química
2.
PLoS Negl Trop Dis ; 14(9): e0008684, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32946436

RESUMO

Leishmania tropica is one of the main causative agents of cutaneous leishmaniasis (CL). Population structures of L. tropica appear to be genetically highly diverse. However, the relationship between L. tropica strains genomic diversity, protein coding gene evolution and biogeography are still poorly understood. In this study, we sequenced the genomes of three new clinical L. tropica isolates, two derived from a recent outbreak of CL in camps hosting Syrian refugees in Lebanon and one historical isolate from Azerbaijan to further refine comparative genome analyses. In silico multilocus microsatellite typing (MLMT) was performed to integrate the current diversity of genome sequence data in the wider available MLMT genetic population framework. Single nucleotide polymorphism (SNPs), gene copy number variations (CNVs) and chromosome ploidy were investigated across the available 18 L. tropica genomes with a main focus on protein coding genes. MLMT divided the strains in three populations that broadly correlated with their geographical distribution but not populations defined by SNPs. Unique SNPs profiles divided the 18 strains into five populations based on principal component analysis. Gene ontology enrichment analysis of the protein coding genes with population specific SNPs profiles revealed various biological processes, including iron acquisition, sterols synthesis and drug resistance. This study further highlights the complex links between L. tropica important genomic heterogeneity and the parasite broad geographic distribution. Unique sequence features in protein coding genes identified in distinct populations reveal potential novel markers that could be exploited for the development of more accurate typing schemes to further improve our knowledge of the evolution and epidemiology of the parasite as well as highlighting protein variants of potential functional importance underlying L. tropica specific biology.


Assuntos
Variação Genética , Genoma de Protozoário , Leishmania tropica/genética , Azerbaijão , Variações do Número de Cópias de DNA , DNA de Protozoário/genética , Dosagem de Genes , Mapeamento Geográfico , Humanos , Líbano , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Repetições de Microssatélites , Filogenia , Polimorfismo de Nucleotídeo Único , Refugiados , Síria
3.
PLoS Pathog ; 16(8): e1008810, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817704

RESUMO

Sterol 14-α-demethylase (C14DM) is a key enzyme in the biosynthesis of sterols and the primary target of azoles. In Leishmania major, genetic or chemical inactivation of C14DM leads to accumulation of 14-methylated sterol intermediates and profound plasma membrane abnormalities including increased fluidity and failure to maintain ordered membrane microdomains. These defects likely contribute to the hypersensitivity to heat and severely reduced virulence displayed by the C14DM-null mutants (c14dm‾). In addition to plasma membrane, sterols are present in intracellular organelles. In this study, we investigated the impact of C14DM ablation on mitochondria. Our results demonstrate that c14dm‾ mutants have significantly higher mitochondrial membrane potential than wild type parasites. Such high potential leads to the buildup of reactive oxygen species in the mitochondria, especially under nutrient-limiting conditions. Consistent with these mitochondrial alterations, c14dm‾ mutants show impairment in respiration and are heavily dependent on glucose uptake and glycolysis to generate energy. Consequently, these mutants are extremely sensitive to glucose deprivation and such vulnerability can be rescued through the supplementation of glucose or glycerol. In addition, the accumulation of oxidants may also contribute to the heat sensitivity exhibited by c14dm‾. Finally, genetic or chemical ablation of C14DM causes increased susceptibility to pentamidine, an antimicrobial agent with activity against trypanosomatids. In summary, our investigation reveals that alteration of sterol synthesis can negatively affect multiple cellular processes in Leishmania parasites and make them vulnerable to clinically relevant stress conditions.


Assuntos
Leishmania major/enzimologia , Leishmania major/fisiologia , Leishmaniose Cutânea/patologia , Mitocôndrias/fisiologia , Proteínas de Protozoários/metabolismo , Esterol 14-Desmetilase/metabolismo , Esteróis/metabolismo , Humanos , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Potencial da Membrana Mitocondrial , Proteínas de Protozoários/genética , Espécies Reativas de Oxigênio/metabolismo , Esterol 14-Desmetilase/genética
4.
PLoS Negl Trop Dis ; 14(8): e0008380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797078

RESUMO

In French Guiana, five species are associated with Cutaneous Leishmaniasis (CL). Though infections with Leishmania guyanensis, L. (V.) braziliensis and L. (L.) amazonensis have been extensively described, there are few available clinical and genetic data on L. (V.) lainsoni and L. (V.) naiffi. We determined the clinical and epidemiological features of all cases of CL due to L. (V.) naiffi and L. (V.) lainsoni diagnosed in French Guiana between 2003 and 2019. Phylogenetic analysis was performed by sequencing a portion of HSP70 and cyt b genes. Five cases of L. naiffi and 25 cases of L. lainsoni were reported. Patients infected by L. (V.) lainsoni were usually infected on gold camps, mostly along the Maroni river (60%), while L. naiffi was observed in French patients infected on the coast (100%). A high number of pediatric cases (n = 5; 20%) was observed for L. (V.) lainsoni. A mild clinical course was observed for all cases of L. (V.) naiffi. HSP70 and cyt b partial nucleotide sequence analysis revealed different geographical clusters within L. (V.) naiffi and L. (V.) lainsoni but no association were found between phylogenetic and clinical features. Our data suggest distinct socio-epidemiological features for these two Leishmania species. Patients seem to get infected with L. (V.) naiffi during leisure activities in anthropized coastal areas, while L. (V.) lainsoni shares common features with L. (V.) guyanensis and braziliensis and seems to be acquired during professional activities in primary forest regions. Phylogenetic analysis has provided information on the intraspecific genetic variability of L. (V.) naiffi and L. (V.) lainsoni and how these genotypes are distributed at the geographic level.


Assuntos
Leishmania/classificação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Citocromos b/genética , Feminino , Guiana Francesa/epidemiologia , Proteínas de Choque Térmico HSP70/genética , Humanos , Lactente , Leishmania/genética , Leishmania/patogenicidade , Leishmaniose Cutânea/patologia , Atividades de Lazer , Masculino , Pessoa de Meia-Idade , Mineração , Doenças Negligenciadas , Filogenia , Estudos Retrospectivos , Análise de Sequência de DNA
5.
PLoS Negl Trop Dis ; 14(7): e0008429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687498

RESUMO

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Índia/epidemiologia , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Adulto Jovem
6.
Am J Trop Med Hyg ; 103(4): 1496-1501, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32618254

RESUMO

In the United States, phlebotomine sand flies carrying Leishmania (Leishmania) mexicana are endemic along the southern border. However, relatively little is known about the enzootic and zoonotic transmission of L. (L.) mexicana within the United States, and autochthonous cases of the consequent disease are rarely reported. We investigated an atypical case of cutaneous leishmaniasis (CL) caused by L. (L.) mexicana in a patient from central Texas which did not respond to a typical antileishmanial chemotherapy. We also investigated sand fly vectors around the patient's residence. PCR followed by DNA sequencing was used for determination of Leishmania spp., sand fly species, and host blood meal source. The L. (L.) mexicana genotype from the patient was identical to one found in a positive sand fly. Moreover, this genotype presented the same single-nucleotide polymorphisms as other historical CL cases acquired in Texas over the last 10 years, but distinct from those originating in Mexico and Central America. Three sand fly species were identified among the samples analyzed (n = 194), the majority of which were Lutzomyia (Dampfomyia) anthophora (n = 190), of which four specimens tested positive for Leishmania and two blood-fed specimens showed the presence of a human blood meal. This study highlights the complexity of clinical management of CL in a setting where the disease is infrequently encountered. The detection of human blood in Lu. (D.) anthophora is the first documentation of anthropophagy in this species. This is the first report of wild-caught, naturally infected sand flies found in association with an autochthonous case of human leishmaniasis and the specific strain of Leishmania (Leishmania) mexicana in the United States.


Assuntos
Insetos Vetores/parasitologia , Leishmania mexicana/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Phlebotomus/parasitologia , Idoso , Animais , Humanos , Leishmania mexicana/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Masculino , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Texas
7.
Clin Dermatol ; 38(2): 140-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32513395

RESUMO

Cutaneous leishmaniasis (CL) is called "the great imitator," because it can mimic almost all types of dermatoses. This similarity may sometimes lead to misdiagnosis, resulting in inappropriate treatment and morbidities. Atypical forms occur due to the interaction between parasitic factors and the host immune response. Secondary infection or mistreatment of CL can also alter the natural course, resulting in bizarre and misdiagnosed cases. Atypical leishmaniasis should be considered in longstanding and painless lesions that may simulate erysipelas, dermatitis, verruca, herpes zoster, paronychia, and sporotrichosis. Less commonly, sarcoidosis, deep mycosis, basal and squamous cell carcinoma, cutaneous lymphoma, or pseudolymphomalike lesions may need to be considered in the differential diagnosis. A high index of suspicion is required to consider a diagnosis of CL, especially in nonendemic or newly endemic regions. Smear, histopathologic examination, culture, and polymerase chain reaction serve as important tools to differentiate CL from its clinical and histologic look-alikes. CL is discussed from various perspectives, with emphasis on CL and its broad differential diagnosis.


Assuntos
Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/patologia , Pele/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Técnicas e Procedimentos Diagnósticos , Humanos , Leishmania/genética , Leishmania/isolamento & purificação , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Reação em Cadeia da Polimerase
9.
Pathologe ; 41(4): 344-354, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32239323

RESUMO

BACKGROUND: An infectious pathogenesis should always be considered in inflammatory infiltrates in the skin. While some organisms can be recognized on hematoxylin-eosin staining (e.g. yeasts, leishmania), histochemical and immunohistochemical stainings are available for others. OBJECTIVES: If no organisms are seen in a section, the diagnosis of an infection cannot be made with surety, but the pattern of the inflammatory infiltrate can still be suggestive of an infectious process. New or little-known reaction patterns and difficulties in differential diagnosis will be demonstrated. MATERIALS AND METHODS: Selective literature review and analysis of individual cases. RESULTS: Studies using molecular techniques to identify organisms in biopsy specimens have helped to better characterize the histomorphological spectrum of skin infiltrates in infectious skin diseases. Apart from unusual herpes simplex and varicella zoster infections, the histopathology of coxsackie virus and measles exanthem, borreliosis, syphilis, and of cutaneous leishmaniasis is demonstrated. For numerous organisms, molecular tests have been established that can be used on the formalin-fixed, paraffin-embedded material. CONCLUSIONS: Selected skin infections demonstrate the broad histomorphological spectrum of skin infiltrates induced by infectious organisms. It is important for histopathologists to know which reaction pattern requires them to alert the clinician to necessary ancillary diagnostics (culture, serology) and when to consider molecular diagnostics to be performed on the biopsy specimen.


Assuntos
Leishmaniose Cutânea , Dermatopatias Infecciosas , Diagnóstico Diferencial , Humanos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/patologia , Reação em Cadeia da Polimerase , Pele , Dermatopatias Infecciosas/diagnóstico , Dermatopatias Infecciosas/patologia
10.
Mem Inst Oswaldo Cruz ; 115: e190361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130370

RESUMO

Genes associated with wound healing have been shown to be risk factors for cutaneous leishmaniasis (CL) which is caused by Leishmania braziliensis. In this study, we examined whether the genes previously associated with CL influenced the clinical outcome. Patients were genotyped and retrospectively classified as responders, who were cured with a single course of pentavalent antimony (Sbv), or as refractories, who did not respond to Sbv. Patients characterised as responders showed a stronger response to the leishmanin skin test (LST) when compared to the refractory subjects (p = 0.0003). Furthermore, we observed an association between the FLI1 CC genotype and an increased size of ulcers (p = 0.0170). We suggest that the leishmanin skin test may be a predictive tool for therapeutic outcome and reinforce FLI1 as a potential influencer of susceptibility and lesion size in CL.


Assuntos
Antimônio/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/genética , Cicatrização/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Testes Cutâneos , Adulto Jovem
11.
Immunology ; 159(4): 355-356, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32182636

RESUMO

Both CD8+ T cells and NK cells contribute to the immune response against the protozoan Leishmania parasite. Both are able to generate IFN-γ and both display cytotoxic features. These features may enable them to not only contribute to parasite clearance but also to cause immune-mediated pathology. This pathology is evident, for example, in the Leismania-induced skin lesions found in patients with cutaneous leismaniasis (CL). Here we highlight new data demonstrating that CD8+ T cells and NK cells in CL display a highly cytotoxic senescent phenotype, and that the senescent T cells play a major role in mediating skin pathology. This is the first demonstration that senescent CD8 T cells contribute to immunopathology in vivo.


Assuntos
Citotoxicidade Imunológica , Leishmania braziliensis/patogenicidade , Leishmaniose Cutânea/patologia , Pele/patologia , Linfócitos T Citotóxicos/patologia , Antígenos CD57/genética , Antígenos CD57/imunologia , Senescência Celular/imunologia , Expressão Gênica , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/parasitologia , Células Matadoras Naturais/patologia , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Oligossacarídeos/genética , Oligossacarídeos/imunologia , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/genética , Antígeno Sialil Lewis X/imunologia , Pele/imunologia , Pele/parasitologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/parasitologia
12.
PLoS One ; 15(3): e0229400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203546

RESUMO

The pathogenesis of cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is dictated mainly by the immune-mediated-tissue inflammation developed. The understanding of the immunological mechanisms that generate tissue damage or resolution of lesions is the key to the development of effective vaccine protocols and proper therapeutic schemes. It is clear that the specific immune response mediated by T cells is responsible for the beneficial outcome of the disease, however, the roles of CD4+ T, CD8+ T, NK and NKT cell subpopulations in immunopathogenesis of CL need to be elucidated. Peripheral blood cells from patients before, during and after the antimonial therapy, as well as healthy individuals (HI) were cultured with (LbAgS) or without (NS) L. braziliensis antigens (LbAg). Afterwards, the frequencies of LbAg-specific-cytotoxic CD8+ T, CD4+ T, NK and CD3+CD56+ NKT cells, as well as their activation and exhaustion profiles, were defined by flow cytometry. We observed higher frequencies of CD8+ T, NK and CD3+CD56+ NKT cells and lower frequencies of CD4+ T lymphocytes in LbAgS cell cultures from patients before treatment. The specific response to LbAg resulted in an expansion of cytotoxic-activated CD4+ T, CD8+ T, and NK cells, before and during treatment, indicating specificity in the response by these cells against L. braziliensis. Furthermore, comparing the differences of frequencies of cytotoxic-activated CD4+T, CD8+T, and NK cells, among before and during treatment patients and HI groups, we conclude that these cell populations are in charge of immune response elicited by antimonial therapy. Interestingly, we also observed that NK cells were induced by LbAg to an exhaustion profile during all clinical stages of the disease. The increased antigen-specific activation and cytotoxic activity are in line with the strong inflammatory response described in this disease, a likely cause of tissue damage. These findings reinforce the involvement of these distinct cytotoxic-activated cell populations in the immunopathogenesis of CL, showing a character of specificity in this immune response.


Assuntos
Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Adulto , Idoso , Complexo CD3/metabolismo , Antígeno CD56/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos , Adulto Jovem
13.
PLoS Negl Trop Dis ; 14(2): e0007996, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092059

RESUMO

BACKGROUND: Cutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients' expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers' community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials. METHODOLOGY/PRINCIPAL FINDINGS: We report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae. CONCLUSIONS/SIGNIFICANCE: The study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar formation, such as social stigmatization and disability. In addition, patients should be given information in order to clarify reported misconceptions. This study therefore suggests a methodology for consulting CL patients on outcomes as elements of clinical trial design, and how to incorporate these outcomes in trials. It also discusses how reported outcomes could be addressed in clinical care.


Assuntos
Antiprotozoários/uso terapêutico , Saúde Global , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Preferência do Paciente , Coleta de Dados , Humanos , Pesquisa Qualitativa , Qualidade de Vida , Resultado do Tratamento
14.
Am J Trop Med Hyg ; 102(4): 777-781, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32043440

RESUMO

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis occurs predominantly in adult males. Herein, we compare the clinical presentation and the response to antimony therapy of CL in children versus adults. Participants included 571 patients with CL; of these, 129 were children (age ≤ 12 years). Cure was defined as the complete healing of ulcer in the absence of raised borders at day 90 after initiation of therapy. Failure was defined by the presence of an active ulcer or a scar with elevated borders at day 90. In comparison with adults, children had shorter duration of illness, more lesions in the head, and smaller ulcers. Risk factors for therapeutic failure were younger age, shorter duration of disease, higher number of lesions, and larger size of the biggest ulcer. When age was categorized in ≤ 12-year-olds (children versus adults), it predicted therapeutic failure with statistical significance at day 60 but not at day 90. In conclusion, our data indicate that there are significant differences in the clinical presentation of CL between children and adults. Physicians caring for children with CL should be aware that lesions may take longer to heal and remain alert for the possibility of higher odds of therapeutic failure in this group.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Antimoniato de Meglumina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade
15.
PLoS Negl Trop Dis ; 14(1): e0007981, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961871

RESUMO

BACKGROUND: Molecular diagnostic tests, notably polymerase chain reaction (PCR), are highly sensitive test for Leishmania detection, which is especially relevant in chronic cutaneous lesion with lower parasite load. An accurate diagnosis is essential because of the high toxicity of the medications for the disease. Nevertheless, diagnosis of cutaneous leishmaniasis (CL) is hampered by the absence of a reference standard. Assuming that the PCR-based molecular tools are the most accurate diagnostic method, the objective of this systematic review was to assess the diagnostic accuracy of PCR-based molecular tools in a meta-analysis of the published literature. METHODOLOGY/PRINCIPAL FINDINGS: A search of the published literature found 142 papers of which only 13 studies met the selection criteria, including conventional PCR, real-time PCR, Loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA), polymorphism-specific PCR (PS-PCR). The sensitivities of the individual studies ranged from 61% to 100%, and specificities ranged from 11% to 100%. The pooled sensitivities of PCR in smears were 0.95 (95% CI, 0.90 to 0.98), and the specificity was 0.91(95% CI, 0.70 to 0.98). In general population, estimates were lower in aspirates, skin biopsies and swab samples with 0.90 (95% CI, 0.80 to 0.95) and 0.87 (95% CI, 0.76 to 0.94) for sensitivity and specificity, respectively. The specificity was lower in consecutive studies, at 0.88 (95% CI, 0.59 to 0.98) and its CI were wider. CONCLUSIONS/SIGNIFICANCE: No statistically significant differences between the accuracy in smears, aspirate, skin biopsies or swabs samples were observed. Therefore, a simple smear sample run by PCR, instead more invasive samples, may be enough to obtain a positive diagnosis of CL. The results for PCR in all samples type confirm previous reports that consider PCR as the most accurate method for the diagnosis of CL.


Assuntos
Testes Diagnósticos de Rotina/métodos , Leishmania/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Biópsia , Humanos , Leishmania/classificação , Leishmania/genética , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Sensibilidade e Especificidade , Pele/parasitologia
16.
Rev Soc Bras Med Trop ; 53: e20190380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994668

RESUMO

Tegumentary leishmaniasis (TL) diagnosis is challenging due to the lack of a gold standard diagnostic tool. The diagnosis is significantly harder in regions where visceral leishmaniasis (VL) is also prevalent since immunological tests may present cross-reactivity. A cirrhotic patient from an endemic Brazilian region for TL and VL presented with atypical cutaneous lesions, a usual clinico-laboratory feature of VL (including a positive rk39 test result), but he was diagnosed with TL histopathologically; VL was ruled out by necropsy. Physicians working in co-prevalent areas should be aware of atypical features, unusual clinical course, and unexpected laboratory findings of leishmaniasis.


Assuntos
Leishmaniose Cutânea/patologia , Leishmaniose Visceral/diagnóstico , Cirrose Hepática/complicações , Diagnóstico Diferencial , Evolução Fatal , Humanos , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/diagnóstico , Masculino , Pessoa de Meia-Idade
17.
Immunology ; 159(4): 429-440, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31925782

RESUMO

Cytotoxic activity mediated by CD8+ T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age-matched controls. The accumulation of circulating senescent NK cells (CD56dim  CD57bright ) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8+ T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin-homing potential compared with total or senescent CD8+ T cells. This was confirmed in CL skin lesions where we found a predominance of CD8+ T cells (both senescent and non-senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56+  CD57+ ) in the skin and lesion size, this was less evident. Collectively our results demonstrate first-hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8+ T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non-specific skin damage in CL.


Assuntos
Citotoxicidade Imunológica , Células Matadoras Naturais/patologia , Leishmania braziliensis/patogenicidade , Leishmaniose Cutânea/patologia , Pele/patologia , Linfócitos T Citotóxicos/patologia , Antígeno CD56/genética , Antígeno CD56/imunologia , Antígenos CD57/genética , Antígenos CD57/imunologia , Estudos de Casos e Controles , Senescência Celular/imunologia , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/parasitologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Masculino , Oligossacarídeos/genética , Oligossacarídeos/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Índice de Gravidade de Doença , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/genética , Antígeno Sialil Lewis X/imunologia , Transdução de Sinais , Pele/imunologia , Pele/parasitologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/parasitologia
18.
BMC Vet Res ; 16(1): 13, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931804

RESUMO

BACKGROUND: Leishmaniasis is a emergent disease characterized by different clinical manifestations in both humans and dogs. Predominant clinical features of cutaneous leishmaniasis are ulcerative painless skin lesions. Several data reported that pain is associated with human and dog leishmaniasis, out with areas of painless ulcerative lesions per se. Actually, current medications used for leishmaniasis management are characterized by several side effects and, in addition, some cases of the disease are refractory to the treatment. On this background it is mandatory the identification of new and safe candidates for designing less toxic and low-cost remedies. Therefore, the search for new leishmanicidal compounds is indispensable. METHODS: In the present paper we investigated the effect of orally N-acetyl-L-cysteine (NAC) supplementation at dose of 200 mg/Kg for 10 weeks, in subcutaneous Leishmania (L). amazonensis infected BALB/c mice. And evaluating the effect of NAC on inflammatory response such as TNF-α, IL-6, IL-1ß levels, and on thermal and mechanical hyperalgesia. RESULTS: In the present paper we showed how NAC supplementation affected parameters of oxidative stress (GSH, MDA, SOD), inflammation such as cytokines levels (IL-1ß, IL-6, TNFα) and mast cell activation and consequently on induced pain, during leishmaniosis in BALB\c mice. CONCLUSIONS: The findings of our study provided the scientific data demonstrating that L. amazonensis infection induces inflammation and pain in BALB/c mice that are reversed by administration of NAC.


Assuntos
Acetilcisteína/farmacologia , Inflamação/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Animais , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/patologia , Masculino , Mastocitose/tratamento farmacológico , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos
19.
Parasit Vectors ; 13(1): 24, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931865

RESUMO

BACKGROUND: Leishmaniasis, considered by the World Health Organization as one of the most important tropical diseases, is endemic in the Mediterranean Basin. The aim of this study was to evaluate epidemiological and clinical characteristics of cutaneous (CL) and mucocutaneous leishmaniasis (MCL) in La Fe University Hospital, Valencia, Spain. The particular focus was on diagnosis techniques and clinical differences according to the immunological status of the patients. METHODS: An eleven-year retrospective observational study of CL and MCL episodes at the hospital was performed. Epidemiological, clinical and therapeutic variables of each case, together with the microbiological and anatomopathological diagnosis, were analyzed. RESULTS: A total of 42 patients were included, 30 of them were male and 28 were immunocompetent. Most of the cases (36/42) were diagnosed in the last 5 years (2013-2017). The incidence of CL and MCL increased from 3.6/100,000 (2006-2012) to 13.58/100,000 (2013-2017). The majority of the patients (37/42) exhibited CL, in 30 cases as single lesions (30/37). Ulcerative lesions were more common in immunosuppressed patients (13/14) than in immunocompetent patients (20/28), (P = 0.2302). The length of lesion presence before diagnosis was 7.36 ± 6.72 months in immunocompetent patients and 8.79 ± 6.9 months in immunosuppressed patients (P = 0.1863). Leishmania DNA detection (92.3%) was the most sensitive diagnostic technique followed by Giemsa stain (65%) and histopathological examination (53.8%). Twelve patients (12/42) had close contact with dogs or were living near to kennels, and 10 of them did not present underlying conditions. Intralesional glucantime (21/42) and liposomal amphotericin B (7/42) were the most common treatments administered in monotherapy. All patients evolved successfully and no relapse was reported. CONCLUSIONS: Some interesting clinical and epidemiological differences were found in our series between immunocompetent and immunosuppressed patients. Future studies can take these results further especially by studying patients with biological therapy. Skin biopsies combining NAAT with histological techniques are the most productive techniques for CL or MCL diagnosis.


Assuntos
Leishmania/efeitos dos fármacos , Leishmaniose Cutânea , Leishmaniose Mucocutânea , Administração Cutânea , Adolescente , Adulto , Idoso , Anfotericina B/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Hospedeiro Imunocomprometido , Leishmania/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Leishmaniose Mucocutânea/diagnóstico , Leishmaniose Mucocutânea/tratamento farmacológico , Leishmaniose Mucocutânea/imunologia , Leishmaniose Mucocutânea/patologia , Masculino , Antimoniato de Meglumina/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Adulto Jovem
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