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1.
Rev Chilena Infectol ; 38(4): 532-539, 2021 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-34652399

RESUMO

BACKGROUND: Leprosy, a chronic infectious disease, is one of the major causes of preventable disability. Early treatment prevents neurological damage and disability. AIM: To identify prognostic factors of disability in individuals with multibacillary and paucibacillary leprosy who completed a drug treatment between 2011 and 2017 in Paraguay. METHODS: A case-control study was carried out on 34 patients, of them 9 were cases and 25 controls. Cases were those patients with Grade 1, presented lack of sensation in lower or upper limbs, and those of Grade 2 lagophthalmos, rigidity, visible deformity ulcerations, passive claw, active claw. Controls had no disabilities. RESULTS: Mean age of the patients was 53 ± 15.2 years, 55.9% were male, and 58.9% had primary education or no formal education. Multibacillary leprosy was found in 58.8% of patients; and 64.7% were diagnosed after consulting with two or more physicians. Diagnosis delay of more than one year was significantly (p = 0.047) greater in the cases than in the controls (77.8% vs 12%; OR: 7.44; 95% CI: 1.02-67.86). CONCLUSION: In this study, a diagnosis delay of more than one year is a prognostic factor for disability.


Assuntos
Hanseníase , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Paraguai/epidemiologia , Prognóstico
2.
PLoS Negl Trop Dis ; 15(8): e0009434, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34449765

RESUMO

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.


Assuntos
Malária/genética , Polimorfismo de Nucleotídeo Único , Piruvato Quinase/genética , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Moçambique , Piruvato Quinase/deficiência , Adulto Jovem
3.
PLoS Negl Trop Dis ; 15(6): e0009456, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34166403

RESUMO

BACKGROUND: Ethiopia has over 3,200 new cases of leprosy diagnosed every year. Prevention remains a challenge as transmission pathways are poorly understood. Susceptibility and disease manifestations are highly dependent on individual host-immune response. Nutritional deficiencies, such as protein-energy malnutrition, have been linked to reduced cell-mediated immunity, which in the case of leprosy, could lead to a higher chance of active leprosy and thus an increased reservoir of transmissible infection. METHODOLOGY/PRINCIPAL FINDINGS: Between June and August 2018, recently diagnosed patients with leprosy and individuals without known contact with cases were enrolled as controls in North Gondar regional health centers. Participants answered survey questions on biometric data, demographics, socioeconomic situation, and dietary habits. Descriptive statistics, univariate, and multivariate logisitic regression examined associations between undernutrition, specifically body mass index (BMI), middle upper arm circumference (MUAC), and leprosy. Eighty-one participants (40 cases of leprosy, 41 controls) were enrolled (75% male) with an average age of 38.6 years (SD 18.3). The majority of cases were multibacillary (MB) (90%). There was a high prevalence of undernutrition with 24 (29.6%) participants underweight (BMI <18.5) and 17 (21%) having a low MUAC. On multivariate analysis, underweight was significantly associated with leprosy (aOR = 9.25, 95% CI 2.77, 30.81). Also found to be associated with leprosy was cutting the size of meals/skipping meals (OR = 2.9, 95% CI 1.0, 8.32) or not having enough money for food (OR = 10, 95% CI 3.44 29.06). CONCLUSIONS/SIGNIFICANCE: The results suggest a strong association between leprosy and undernutrition, while also supporting the framework that food insecurity may lead to undernutrition that then could increase susceptibility to leprosy. In conclusion, this study highlights the need to study the interplay of undernutrition, food insecurity, and the manifestations of leprosy.


Assuntos
Insegurança Alimentar/economia , Hanseníase/epidemiologia , Hanseníase/etiologia , Desnutrição/complicações , Desnutrição/epidemiologia , Pobreza , Adulto , Estudos de Casos e Controles , Etiópia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
4.
Indian J Dermatol Venereol Leprol ; 87(3): 357-363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33871214

RESUMO

BACKGROUND: Carotid intima-media thickness test is a surrogate marker of subclinical atherosclerosis. Epicardial fat thickness is an early marker of coronary artery disease. Several studies have noted that psoriasis patients have an increased risk of coronary artery disease. In the present study, we attempted to see any variation in carotid intima-media thickness and epicardial fat thickness in psoriasis patients when compared to controls. AIMS: 1) To determine the carotid intima-media thickness and epicardial fat thickness in psoriatic patients and healthy controls. 2) To evaluate the association between carotid intima-media thickness and epicardial fat thickness in psoriasis patients. METHODS: A hospital-based study with 100 subjects (50 with psoriasis and 50 healthy controls) was conducted in the Dermatology Outpatient Department of Justice KS Hegde Charitable Hospital, a unit of KS Hegde Medical Academy affiliated to NITTE (Deemed to be University) Mangaluru. A detailed history and examination including body mass index, psoriasis area and severity index were done. Carotid ultrasound was done to measure carotid intima-media thickness and transthoracic echocardiography was done to assess epicardial fat thickness in both cases and controls. Independent sample t-test, Pearson rank correlation (r) coefficient were used for statistical analysis. P-value <0.05 was considered statistically significant. IBM Statistical Package for the Social Sciences version 22 Armonk, NY: IBM Corp was used for statistical analysis. RESULTS: Mean carotid intima-media thickness in the right carotid ([0.51 ± 0.1mm vs 0.47 ± 0.1 mm] [P = 0.038]) and left carotid ([0.53 ± 0.12 mm vs 0.48 ± 0.1 mm] [P = 0.041]) were significantly increased in psoriasis patients than in controls. Mean epicardial fat thickness was significantly increased ([1.76 ± 0.66 mm vs. 1.49 ± 0.47 mm] ([P = 0.020]) in patients with psoriasis when compared with the controls. Epicardial fat thickness was positively correlated with carotid intima-media thickness in patients with psoriasis. LIMITATIONS: The cross-sectional design of the study, smoking among study subjects, inter and intraobserver variability of measurement of epicardial fat thickness and carotid intima-media thickness. CONCLUSION: Carotid intima-media thickness and epicardial fat thickness were increased in psoriasis patients when compared with healthy controls. Epicardial fat thickness was positively correlated with carotid intima-media thickness in cases.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Espessura Intima-Media Carotídea , Pericárdio/diagnóstico por imagem , Psoríase/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Pressão Sanguínea , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Estudos Transversais , Ecocardiografia , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Adulto Jovem
5.
PLoS Negl Trop Dis ; 15(3): e0009214, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33690671

RESUMO

BACKGROUND: Leprosy continues to be a public health problem in Brazil. Furthermore, detection rates in elderly people have increased, particularly those of multibacillary (L-Lep) patients, who are responsible for transmitting M. leprae. Part of the decline in physiological function during aging is due to increased oxidative damage and change in T cell subpopulations, which are critical in defense against the disease. It is not still clear how age-related changes like those related to oxidation affect elderly people with leprosy. The aim of this work was to verify whether the elderly leprosy patients have higher ROS production and how it can impact the evolution of leprosy. METHODOLOGY/PRINCIPAL FINDINGS: 87 leprosy patients, grouped according to age range and clinical form of leprosy, and 25 healthy volunteers were analyzed. Gene expression analysis of antioxidant and oxidative burst enzymes were performed in whole blood using Biomark's microfluidic-based qPCR. The same genes were evaluated in skin lesion samples by RT-qPCR. The presence of oxidative damage markers (carbonylated proteins and 4-hydroxynonenal) was analyzed by a DNPH colorimetric assay and immunofluorescence. Carbonylated protein content was significantly higher in elderly compared to young patients. One year after multidrug therapy (MDT) discharge and M. leprae clearance, oxidative damage increased in young L-Lep patients but not in elderly ones. Both elderly T and L-Lep patients present higher 4-HNE in cutaneous lesions than the young, mainly surrounding memory CD8+ T cells. Furthermore, young L-Lep demonstrated greater ability to neutralize ROS compared to elderly L-Lep patients, who presented lower gene expression of antioxidant enzymes, mainly glutathione peroxidase. CONCLUSIONS/SIGNIFICANCE: We conclude that elderly patients present exacerbated oxidative damage both in blood and in skin lesions and that age-related changes can be an important factor in leprosy immunopathogenesis. Ultimately, elderly patients could benefit from co-supplementation of antioxidants concomitant to MDT, to avoid worsening of the disease.


Assuntos
Hansenostáticos/uso terapêutico , Hanseníase/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Aldeídos , Antioxidantes , Carga Bacteriana , Brasil , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae , Estresse Oxidativo , Carbonilação Proteica , Pele/metabolismo , Pele/patologia
6.
Front Immunol ; 12: 647385, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777045

RESUMO

Leprosy is an infectious disease that remains endemic in approximately 100 developing countries, where about 200,000 new cases are diagnosed each year. Moreover, multibacillary leprosy, the most contagious form of the disease, has been detected at continuously higher rates among Brazilian elderly people. Due to the so-called immunosenescence, characterized by several alterations in the quality of the immune response during aging, this group is more susceptible to infectious diseases. In view of such data, the purpose of our work was to investigate if age-related alterations in the immune response could influence the pathogenesis of leprosy. As such, we studied 87 individuals, 62 newly diagnosed and untreated leprosy patients distributed according to the age range and to the clinical forms of the disease and 25 healthy volunteers, who were studied as controls. The frequency of senescent and memory CD8+ leukocytes was assessed by immunofluorescence of biopsies from cutaneous lesions, while the serum levels of IgG anti-CMV antibodies were analyzed by chemiluminescence and the gene expression of T cell receptors' inhibitors by RT-qPCR. We noted an accumulation of memory CD8+ T lymphocytes, as well as reduced CD8+CD28+ cell expression in skin lesions from elderly patients, when compared to younger people. Alterations in LAG3 and PDCD1 gene expression in cutaneous lesions of young MB patients were also observed, when compared to elderly patients. Such data suggest that the age-related alterations of T lymphocyte subsets can facilitate the onset of leprosy in elderly patients, not to mention other chronic inflammatory diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Memória Imunológica , Imunossenescência/imunologia , Hanseníase/imunologia , Mycobacterium leprae , Dermatopatias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Antígenos CD/genética , Estudos de Casos e Controles , Citomegalovirus/imunologia , Feminino , Expressão Gênica , Humanos , Imunoglobulina G/sangue , Hanseníase/sangue , Hanseníase/microbiologia , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Pele/imunologia , Pele/patologia , Dermatopatias/sangue , Dermatopatias/microbiologia , Dermatopatias/patologia , Adulto Jovem
7.
Indian J Dermatol Venereol Leprol ; 87(2): 199-206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33769731

RESUMO

BACKGROUND: Detection of peripheral nerve thickening and nerve function impairment is crucial in the diagnosis and the management of leprosy. AIMS AND OBJECTIVES: (1) To document the cross-sectional area, echotexture and blood flow of peripheral nerves in healthy controls and leprosy cases using high-resolution ultrasound, (2) to compare the sensitivities of clinical examination and high-resolution ultrasound in detecting peripheral nerve thickening in leprosy. METHODS: Peripheral nerves of 30 leprosy patients and 30 age- and sex-matched controls were evaluated clinically and by high-resolution ultrasound. When the cross-sectional area of a peripheral nerve on high-resolution ultrasound in a leprosy patient was more than the calculated upper bound of the 95% confidence interval for mean for that specific nerve in controls, that particular peripheral nerve was considered to be enlarged. RESULTS: Cross-sectional areas more than 7.1 mm2 for the radial nerve, 8.17 mm2 for ulnar, 10.17 mm2 for median, 9.50 mm2 for lateral popliteal and 11.21mm2 for the posterior tibial nerve were considered as nerve thickening on high-resolution ultrasound. High-resolution ultrasound detected 141/300 (47%) nerves enlarged in contrast to the 60 (20%) diagnosed clinically by palpation (P < 0.001). Clinical examination identified thickening in 31/70 (44.3%) nerves in cases with impairment of nerve function and 29/230 (12.6%) in the absence of nerve function impairment. High-resolution ultrasound detected thickening in 50/70 (71.4%) nerves with impairment of function and in 91/230 (39.6%) nerves without any impairment of function. LIMITATION: A single-centre study design was the major study limitation. CONCLUSION: High-resolution ultrasound showed greater sensitivity than clinical examination in detecting peripheral nerve thickening in leprosy cases. High-resolution ultrasound, may therefore improve the sensitivity of the diagnostic criterion of peripheral nerve enlargement in the diagnosis and classification of leprosy.


Assuntos
Hanseníase/diagnóstico , Nervos Periféricos/diagnóstico por imagem , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia , Adulto Jovem
8.
Indian J Dermatol Venereol Leprol ; 87(2): 190-198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33769734

RESUMO

BACKGROUND: Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. AIMS: The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL. METHODS: The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH). RESULTS: Significantly higher levels of serum interleukin-6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH. LIMITATIONS: Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. CONCLUSION: High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.


Assuntos
Eritema Nodoso/sangue , Interleucina-6/sangue , Hanseníase/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue
9.
Dermatol Ther ; 34(2): e14882, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33594711

RESUMO

Reactions in leprosy have an immune mediated pathogenesis. While type 1 reactions are delayed hypersensitivity phenomenon, type 2 reactions are immune complex mediated. Key molecules which mediate the immune insult in lepra reactions require evaluation in order to tailor their therapy and prevent disability. The objective of the study was to evaluate expressions of Cyclooxygenase 2 and Vascular Endothelial Growth Factor in skin biopsies from leprosy patients and correlate their expression with presence of either type 1 or type 2 lepra reactions. This was a case control study. Cyclooxygenase 2 and Vascular Endothelial Growth Factor expression in dermal macrophages and vascular endothelium was assessed immunohistochemically. Biopsies from patients with Non-reactive leprosy and healthy controls were used for comparison. SPSS software was used for statistical analysis. A total of 147 skin biopsies were evaluated, including 18 with Type 1 reaction, 39 Type 2 reaction, 81 non-reactive leprosy and 9 healthy controls. Both Cyclooxygenase 2 and Vascular Endothelial Growth Factor expression were significantly higher in type 1 followed by type 2 reaction as compared to controls. These results may guide us regarding use of Cyclooxygenase 2 and Vascular Endothelial Growth Factor inhibitor drugs which may be a major step in treating reactive leprosy patients and preventing nerve damage and disability.


Assuntos
Ciclo-Oxigenase 2/genética , Hanseníase , Fator A de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Humanos , Pele
10.
Int J Infect Dis ; 105: 261-266, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33592342

RESUMO

BACKGROUND: Evidence suggests that biological mechanisms involved in helminth infections and vitamin deficiencies increase susceptibility to other infections. The aim of this study was to investigate the associations of helminth co-infection and select micronutrient deficiencies with leprosy using a case-control design. METHODS: From 2016 to 2018, individuals aged ≥3 years were recruited at clinics in and around Governador Valadares, Minas Gerais, Brazil in three groups: cases of leprosy, household contacts and community-matched (non-contact) controls. Helminths were diagnosed through stool Kato Katz examination and serum reactivity to anti-soluble adult worm antigen preparation IgG4. Serum ferritin, 25-OH vitamin D and retinol concentrations were measured. Multi-variate logistic regression was conducted to identify associations with active leprosy. RESULTS: Seventy-nine cases of leprosy, 96 household contacts and 81 non-contact controls were recruited; 48.1% of participants were male with a median age of 40 years. Helminths were found in 7.1% of participants on Kato Katz test, all but one of which were Schistosoma mansoni, and 32.3% of participants were positive for S. mansoni serology. On multi-variate analysis, cases were more likely to be infected with helminths (diagnosed by stool) than household contacts [adjusted odds ratio (aOR) 8.69, 95% confidence interval (CI) 1.50-50.51]. Vitamin D deficiency was common, and was more likely in cases compared with non-contact controls (aOR 4.66, 95% CI 1.42,-15.33). Iron deficiency was not associated with leprosy, and vitamin A deficiency was not detected. CONCLUSION: These associations suggest that the immune consequences of schistosomiasis and vitamin D deficiency may increase the risk of active leprosy. Comorbid conditions of poverty deserve further study as addressing co-infections and nutritional deficiencies could be incorporated into programmes to improve leprosy control.


Assuntos
Coinfecção/complicações , Helmintos/fisiologia , Hanseníase/complicações , Mycobacterium leprae/fisiologia , Deficiência de Vitamina D/complicações , Adolescente , Adulto , Idoso , Animais , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Fezes/parasitologia , Feminino , Humanos , Hanseníase/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
11.
Int J Immunogenet ; 48(1): 25-35, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33151039

RESUMO

Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case-control and a family-based study in two endemic populations in Brazil. MICA and HLA-B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR-SSOP-Luminex-based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi-square or Fisher's exact test together with a multivariate analysis. Family-based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002-HLA-B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA-A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA-B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA-B markers rs2596498 and rs2507992, and high LD (R2  = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA-B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.


Assuntos
Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/imunologia , Regiões 3' não Traduzidas/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Doenças Endêmicas , Grupos Étnicos/genética , Éxons/genética , Saúde da Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Hanseníase/epidemiologia , Hanseníase/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Domínios Proteicos , Adulto Jovem
12.
Hum Immunol ; 82(1): 11-18, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33189423

RESUMO

Despite intense efforts, the number of new cases of leprosy has remained significantly high over the past 20 years. Host genetic background is strongly linked to the pathogenesis of this disease, which is caused by Mycobacterium leprae (M. leprae), and there is a consensus that the most significant genetic association with leprosy is attributed to the major histocompatibility complex (MHC). Here, we investigated the association of human leukocyte antigen (HLA) class I and II genes with leprosy in a Brazilian population encompassing 826 individuals from a hyperendemic area of Brazil; HLA typing of class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1) loci was conducted. Initially, the associations were tested using the chi-square test, with p-values adjusted using the false discovery rate (FDR) method. Next, statistically significant signals of the associations were submitted to logistic regression analyses to adjust for sex and molecular ancestry data. The results showed that HLA-C*08, -DPB1*04, and -DPB1*18 were associated with protective effects, while HLA-C*12 and -DPB1*105 were associated with susceptibility to leprosy. Thus, our findings reveal new associations between leprosy and the HLA-DPB1 locus and confirm previous associations between the HLA-C locus and leprosy.


Assuntos
Predisposição Genética para Doença , Antígenos HLA-C/genética , Cadeias beta de HLA-DP/genética , Hanseníase/genética , Adolescente , Adulto , Idoso , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Doenças Endêmicas , Feminino , Loci Gênicos , Antígenos HLA-C/imunologia , Cadeias beta de HLA-DP/imunologia , Humanos , Hanseníase/epidemiologia , Hanseníase/imunologia , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Adulto Jovem
13.
PLoS Negl Trop Dis ; 14(12): e0008883, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33362202

RESUMO

Leprosy is an infectious disease caused by Mycobacterium leprae (M. leprae), with about 210,000 new cases per year worldwide. Although numerous risk loci have been uncovered by genome-wide association studies, the effects of common genetic variants are relatively modest. To identify possible new genetic locus involved in susceptibility to leprosy, whole exome sequencing was performed for 28 subjects including 14 patients and 12 unaffected members from 8 leprosy-affected families as well as another case and an unrelated control, and then the follow-up SNP genotyping of the candidate variants was studied in case-control sample sets. A rare missense variant in mitochondrial ribosomal protein S5 (MRPS5), rs200730619 (c. 95108402T>C [p. Tyr137Cys]) was identified and validated in 369 cases and 270 controls of Chinese descent (Padjusted = 0.006, odds ratio [OR] = 2.74) as a contributing factor to leprosy risk. Moreover, the mRNA level of MRPS5 was downregulated in M. leprae sonicate-stimulated peripheral blood mononuclear cells. Our results indicated that MRPS5 may be involved in leprosy pathogenesis. Further studies are needed to determine if defective MRPS5 could lead to impairment of energy metabolism of host immune cells, which could further cause defect in clearing M. leprae and increase susceptibility to infection.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Hanseníase/genética , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único , Proteínas Ribossômicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China/epidemiologia , Feminino , Regulação da Expressão Gênica , Humanos , Hanseníase/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Front Immunol ; 11: 1927, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013845

RESUMO

Mannose-binding lectin (MBL) is a serum protein of innate immunity, with a central role in the activation of the complement system through the lectin pathway. This protein is encoded by MBL2 gene, and single-nucleotide polymorphisms located at exon 1, such as rs5030737 C>T (D variant), rs1800450 G>A (B variant), and rs1800451 G>A (C variant), may change the MBL structure and the serum concentration. MBL2 polymorphisms have been associated with several infectious diseases, including leprosy. Host immune response has a major impact on the clinical manifestation of leprosy since only a few individuals infected with Mycobacterium leprae will develop the disease. Therefore, the aim of this study was to evaluate the influence of MBL2 exon 1 polymorphisms (rs5030737, rs1800450, and rs1800451) on the MBL levels and leprosy immunopathogenesis. This case-control study included 350 leprosy patients from Southern Brazil, with 279 classified as multibacillary (MB) and 71 as paucibacillary (PB). The control group consisted of 350 non-consanguineous individuals, who were not diagnosed with leprosy or other infectious and autoimmune diseases. Genotyping was performed by PCR-sequence specific primers, and the MBL serum concentrations were evaluated by ELISA. MBL2 exon 1 polymorphisms were analyzed individually and grouped as genotypes, considering "A" as the wild allele and "O" as the presence of at least one polymorphism (D, B, or C variants). Differences were not observed in the distribution of genotypic and allelic frequencies between leprosy per se patients and controls. However, in a haplotypic analysis, the TGG haplotype presented a risk for development of leprosy per se in women when compared to the wild haplotype (CGG) (OR = 2.69). Comparing patients with MB and PB, in a multivariate analysis, the B variant was associated with the susceptibility of developing the MB form of leprosy (OR = 2.55). Besides that, the CAG haplotype showed an increased susceptibility to develop MB leprosy in women compared to men. It was observed that the A/O genotype in women was associated with a susceptibility to leprosy development per se (OR = 1.66) and progression to MB leprosy (OR = 3.13). In addition, the MBL serum concentrations were in accordance with the genotyping analysis. In summary, our data suggest that MBL2 exon 1 polymorphisms are associated with an increased risk to leprosy development and progression.


Assuntos
Hanseníase Multibacilar/genética , Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Éxons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hanseníase Multibacilar/diagnóstico , Hanseníase Multibacilar/microbiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais
15.
PLoS Negl Trop Dis ; 14(10): e0008749, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33044965

RESUMO

Leprosy reduces quality of life of affected persons. Oxidative stress caused by reactive oxygen species may play a vital role in the pathogenesis of leprosy. This study evaluated anthropometric indices, fasting plasma glucose (FPG), lipid profile, total antioxidant capacity (TAC), total plasma peroxide (TPP), oxidative stress index (OSI), malondialdehyde (MDA), glutathione (GSH) and 8-hydroxy-2-deoxyguanosine (8-OHdg) in leprosy patients. Sixty test participants of both genders, aged 18-65years and diagnosed of multibacillary leprosy and 30 apparently healthy controls were consecutively recruited for this study. The test participants comprised of 30 patients on multidrug therapy (MDT) and 30 patients relieved from therapy (RFT). Body mass index (BMI), Waist-hip ratio (WHR), FPG, lipid profile, TAC, TPP, OSI, MDA, GSH and 8-OHdg were determined using appropriate methods. Data were analyzed using Analysis of variance; p<0.05 was considered statistically significant. The MDT group had significantly lower BMI (p = 0.0001), Total cholesterol (p = 0.001), HDL-C (p = 0.019), LDL-C (p = 0.005), TAC (p = 0.0001) and higher TPP (p = 0.001), MDA (p = 0.0001), OSI (p = 0.005) and 8-OHdg (p = 0.035) compared to the controls. The RFT group had significantly lower BMI (p = 0.001) Total cholesterol (0.0001), HDL-C (p = 0.006) LDL-C (p = 0.0001), TAC (p = 0.001) and higher WHR (p = 0.010), VLDL-C (p = 0.035), TG (p = 0.023) Atherogenic index of plasma (p = 0.0001) and TPP (p = 0.001), MDA (p = 0.0001) compared to the control group. GSH levels correlated negatively with duration of treatment (r = -0.401, p = 0.028). This study has shown that there is oxidative stress in multibacillary leprosy patients irrespective of drug treatment status. This study also shows that leprosy patients relieved from treatment may be susceptible to cardiovascular events. Antioxidants supplementation may be beneficial in the treatment of leprosy and clinical follow up on patients relieved from treatment may also be necessary to monitor health status and prevent development of cardiovascular events.


Assuntos
Doenças Cardiovasculares/microbiologia , Dano ao DNA , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Estresse Oxidativo , Adulto , Antioxidantes/metabolismo , Biomarcadores/sangue , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Glutationa/sangue , Humanos , Hanseníase/sangue , Masculino , Malondialdeído/farmacologia , Pessoa de Meia-Idade , Nigéria , Fatores de Risco , Adulto Jovem
16.
PLoS Negl Trop Dis ; 14(10): e0008746, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33064728

RESUMO

Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, especially in Papua Island, leprosy is still a problem. Furthermore, there had been higher reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. Globally, DHS has a prevalence rate of 1.4% and a fatality rate up to 13%. The aim of this study is to validate HLA-B*13:01, a previously discovered biomarker for DHS in the Chinese population, as a biomarker for DHS in the Papua population.This is a case-control study of 34 leprosy patients who presented themselves with DHS (case subjects) and 52 leprosy patients without DHS (control subjects). Patients were recruited from 2 provinces: Papua and West Papua. DNA was extracted from 3 ml blood specimens. HLA-B alleles were typed using the gold-standard sequence based typing method. Results were then analysed using logistic regression and risk assessment was carried out. The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio = 233.64 and P-value = 7.11×10-9, confirming the strong association of HLA-B*13:01 to DHS in the Papua population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Papua, Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future.


Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Antígeno HLA-B13/genética , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adolescente , Adulto , Alelos , Biomarcadores , Estudos de Casos e Controles , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Hipersensibilidade a Drogas/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Indonésia , Hansenostáticos/administração & dosagem , Modelos Logísticos , Masculino , Rifampina/administração & dosagem , Medição de Risco , Síndrome , Adulto Jovem
17.
Front Immunol ; 11: 1974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849660

RESUMO

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Cytokines are known to play vital role as a peacekeeper during inflammatory and other immunocompromised conditions such as leprosy. This study has tried to bridge the gap of information on cytokine gene polymorphisms and its potential role in the pathogenesis of leprosy. Interleukin-10 (IL-10) is an immunosuppressive cytokine, found to be elevated in leprosy that accounted for the suppression of host's immune system by regulating the functions of other immune cells. T helper cells and T regulatory (Tregs) cells are the major source of IL-10 in lepromatous leprosy patients. In this study, we have documented the association of IL-10 cytokine gene polymorphism with the disease progression. A total of 132 lepromatous leprosy patients and 120 healthy controls were analyzed for IL-10 cytokine gene polymorphisms using PCR-SSP assay and flow cytometry was used to analyze IL-10 secretion by CD4 and Tregs in various genotype of leprosy patients. The frequencies of IL-10 (-819) TT and IL-10 (-1082) GG genotypes were significantly higher in leprosy patients as compared to healthy controls. This observation advocates that these genotypes were associated with the susceptibility and development of the disease. In addition, flow cytometry analysis demonstrated an increased number of IL-10 producing CD4 and Treg cells in IL-10 (819) TT genotype compared to CT and CC genotypes. These observations were further supported by immunohistochemical studies. Therefore, we can conclude that IL-10 cytokine gene polymorphisms by affecting its production can determine the predilection and progression of leprosy in the study population.


Assuntos
Suscetibilidade a Doenças , Interleucina-10/biossíntese , Interleucina-10/genética , Hanseníase/etiologia , Polimorfismo de Nucleotídeo Único , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Alelos , Estudos de Casos e Controles , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Feminino , Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hanseníase/diagnóstico , Hanseníase/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-32825398

RESUMO

Access to safe water, sanitation, and hygiene (WASH) is critical for preventing the spread of neglected tropical diseases (NTDs) including leprosy. WASH-related transmission factors remain largely unexplored in the leprosy transmission cycle. The aim of this project is to better understand WASH exposures among leprosy cases through a case-control study in North Gondar, Ethiopia. We hypothesized that leprosy cases were more likely to have inadequate WASH access and were more likely to have concurrent schistosomiasis, as schistosomiasis immune consequences may facilitate leprosy infection. Forty leprosy cases (forty-one controls) were enrolled, tested for Schistosomamansoni, administered a demographic and WASH survey, and assigned a WASH index score. WASH factors significantly associated with leprosy on adjusted analyses included open defecation (aOR = 19.9, 95% CI 2.2, 176.3) and lack of access to soap (aOR = 7.3, 95% CI 1.1, 49.9). S. mansoni was detected in 26% of participants and in stratified analysis those with leprosy had a 3.6 (95% CI (0.8, 15.9)) greater odds of schistosomiasis in districts bordering the lake, compared to 0.33 lower odds of schistosomiasis in districts not bordering the lake (95% CI (0.09, 1.2)). Overall, results suggest that leprosy transmission may be related to WASH adequacy and access as well as to schistosomiasis co-infection.


Assuntos
Higiene , Hanseníase , Saneamento , Abastecimento de Água , Adolescente , Adulto , Estudos de Casos e Controles , Etiópia/epidemiologia , Feminino , Humanos , Hanseníase/epidemiologia , Masculino , Pessoa de Meia-Idade , Água , Adulto Jovem
19.
Sci Rep ; 10(1): 12648, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724108

RESUMO

Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.


Assuntos
Transição Epitelial-Mesenquimal , Hanseníase/genética , Hanseníase/patologia , Mycobacterium leprae/patogenicidade , Neuralgia/patologia , RNA Interferente Pequeno/genética , Células de Schwann/patologia , Estudos de Casos e Controles , Doenças Desmielinizantes , Epigênese Genética , Humanos , Hanseníase/microbiologia , Neuralgia/metabolismo , Neuralgia/microbiologia , Células de Schwann/metabolismo , Células de Schwann/microbiologia
20.
Rev Soc Bras Med Trop ; 53: e20200114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32491105

RESUMO

INTRODUCTION: Although supervised doses are essential for reducing leprosy treatment failure, the impact of specific drug interactions has rarely been assessed. This study aimed to estimate the risk of leprosy treatment suspension in patients receiving polypharmacy. METHODS We performed this case-control study in which the primary outcome was defined as the need to discontinue multibacillary leprosy treatment for at least one supervised dose, and the main risk factor was the detection of polypharmacy. Multivariate analysis by logistic regression was used for calculating odds ratio (OR). RESULTS: This study included 103 patients, of whom 43 needed to discontinue leprosy treatment (hemolysis = 26, hepatitis = 2, hemolysis associated with hepatitis = 6, and suspected treatment resistance = 9) and the rest did not. The severity of drug interactions had no effect on treatment discontinuation. Patients who used five or more drugs in addition to leprosy treatment had almost a 4-fold greater risk of treatment suspension (OR, 3.88; 95% confidence interval: 1.79-9.12; p < 0.001). The number of drugs used also positively influenced the occurrence of hemolysis (p < 0.001). No patient presented evidence of molecular resistance to rifampicin, dapsone, or ofloxacin treatment, as evidenced by genetic sequencing detection of rpoB, folp1, and gyrA mutations. CONCLUSIONS: Polypharmacy has deleterious effects on the already difficult-to-adhere-to treatment of leprosy and polypharmacy induces hemolysis. Additional measures must be taken to avoid the undesirable effects of inadequate polypharmacy.


Assuntos
Interações Medicamentosas , Hansenostáticos/administração & dosagem , Hanseníase/tratamento farmacológico , Polimedicação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Hansenostáticos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
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