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1.
PLoS Negl Trop Dis ; 12(3): e0006214, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29565968

RESUMEN

BACKGROUND: Leprosy is a chronic dermato-neurological disease caused by Mycobacterium leprae infection. In 2016, more than 200,000 new cases of leprosy were detected around the world, representing the most frequent cause of infectious irreversible deformities and disabilities. PRINCIPAL FINDINGS: In the present work, we demonstrate a consistent procoagulant profile on 40 reactional and non-reactional multibacillary leprosy patients. A retrospective analysis in search of signs of coagulation abnormalities among 638 leprosy patients identified 35 leprosy patients (5.48%) which displayed a characteristic lipid-like clot formed between blood clot and serum during serum harvesting, herein named 'leprosum clot'. Most of these patients (n = 16, 45.7%) belonged to the lepromatous leprosy pole of the disease. In addition, formation of the leprosum clot was directly correlated with increased plasma levels of soluble tissue factor and von Willebrand factor. High performance thin layer chromatography demonstrated a high content of neutral lipids in the leprosum clot, and proteomic analysis demonstrated that the leprosum clot presented in these patients is highly enriched in fibrin. Remarkably, differential 2D-proteomics analysis between leprosum clots and control clots identified two proteins present only in leprosy patients clots: complement component 3 and 4 and inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP). In agreement with those observations we demonstrated that M. leprae induces hepatocytes release of IHRP in vitro. CONCLUSIONS: We demonstrated that leprosy MB patients develop a procoagulant status due to high levels of plasmatic fibrinogen, anti-cardiolipin antibodies, von Willebrand factor and soluble tissue factor. We propose that some of these components, fibrinogen for example, presents potential as predictive biomarkers of leprosy reactions, generating tools for earlier diagnosis and treatment of these events.


Asunto(s)
Trastornos de la Coagulación Sanguínea/microbiología , Eritema Nudoso/sangre , Lepra Lepromatosa/sangre , Piel/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Brasil , Niño , Electroforesis en Gel Bidimensional , Electroforesis en Gel de Poliacrilamida , Eritema Nudoso/complicaciones , Femenino , Humanos , Lepra Lepromatosa/complicaciones , Modelos Lineales , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Mycobacterium leprae/aislamiento & purificación , Estudios Prospectivos , Proteómica/métodos , Estudios Retrospectivos , Adulto Joven
2.
s.l; s.n; 2018. 20 p. ilus, tab, graf.
No convencional en Inglés | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1023805

RESUMEN

Hemostatic illnesses are frequently associated with acute and chronic infections. In the present work we demonstrated that leprosy patients developed hemostatic abnormalities, like the formation of an atypical lipid clot mass during sera harvesting, a phenomenon previously observed and never unraveled. We characterize the nature of the "leprosum clot", formed during a protrombotic state developed by some patients. During the proteomic analysis of the leprosum clot we discovered a set of potential serum biomarkers to leprosy reactional episodes diagnosis, which at this moment is based only in clinical features. Taking together, our data suggest that leprosy patients are suffering from a procoagulant status, being beneficiated by the introduction of routine coagulation tests during their treatment, which will aloud physicians to prevent some of the acute clinical symptoms related with superficial vein thrombosis such as cyanosis and tissue necrosis observed during severe cases of leprosy reactional episodes. (AU)


Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Piel/microbiología , Espectrometría de Masas , Trastornos de la Coagulación Sanguínea/microbiología , Biomarcadores/sangre , Electroforesis en Gel Bidimensional , Lepra Lepromatosa/complicaciones , Lepra Lepromatosa/sangre , Modelos Lineales , Proteómica/métodos , Electroforesis en Gel de Poliacrilamida , Eritema Nudoso/complicaciones , Eritema Nudoso/sangre , Mycobacterium leprae/aislamiento & purificación , Estudios Prospectivos , Estudios Retrospectivos
3.
PLoS Negl Trop Dis ; 10(10): e0005059, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27732610

RESUMEN

OBJECTIVE: We evaluated the profile of patients referred to the Fiocruz Outpatient Clinic, a reference center for the diagnosis and treatment of leprosy in Rio de Janeiro, RJ, and analyzed the origins and outcomes of these referrals. METHODS: This is an observational retrospective study based on information collected from the Leprosy Laboratory database at Fiocruz, Rio de Janeiro, RJ, Brazil. A total of 1,845 suspected leprosy cases examined at the reference center between 2010 and 2014 were included. The originating health service referrals and diagnostic outcomes were analyzed as well as the clinical and epidemiological data of patients diagnosed with leprosy. RESULT: Our data show that the profile of the patients treated at the Clinic has changed in recent years. There was an increase in both the proportion of patients with other skin diseases and those who had visited only one health service prior to our Clinic. Among the total 1,845 cases analyzed, the outcomes of 1,380 were linked to other diseases and, in 74% of these cases, a biopsy was not necessary to reach a diagnostic conclusion. A decrease in new leprosy case detection among our patients was also observed. Yet, among the leprosy patients, 40% had some degree of disability at diagnosis. CONCLUSION: The results of the present study demonstrated the importance of referral centers in support of basic health services within the decentralization strategy. But, the success of the program depends on the advent of new developmental tools to augment diagnostic accuracy for leprosy. However, it should be emphasized that for new diagnostic methods to be developed, a greater commitment on the part of the health care system regarding research is urgently needed.


Asunto(s)
Lepra/terapia , Instituciones de Atención Ambulatoria/organización & administración , Brasil/epidemiología , Humanos , Lepra/diagnóstico , Lepra/epidemiología , Salud Pública , Derivación y Consulta , Estudios Retrospectivos
4.
Antimicrob Agents Chemother ; 58(10): 5766-74, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25049257

RESUMEN

Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.


Asunto(s)
Antituberculosos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/patogenicidad , Rifampin/uso terapéutico , Animales , Atorvastatina , Línea Celular , Sinergismo Farmacológico , Ácidos Heptanoicos/uso terapéutico , Humanos , Lepra/tratamiento farmacológico , Macrófagos/microbiología , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Pirroles/uso terapéutico , Simvastatina/uso terapéutico
5.
s.l; s.n; 2014. 9 p. ilus, graf.
No convencional en Inglés | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1095830

RESUMEN

Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.


Asunto(s)
Humanos , Animales , Ratones , Pirroles/uso terapéutico , Rifampin/uso terapéutico , Línea Celular , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Simvastatina/uso terapéutico , Sinergismo Farmacológico , Atorvastatina , Ácidos Heptanoicos/uso terapéutico , Lepra/tratamiento farmacológico , Macrófagos/microbiología , Ratones Endogámicos BALB C , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/patogenicidad , Mycobacterium tuberculosis/patogenicidad , Antituberculosos/uso terapéutico
6.
Trop Med Int Health ; 18(9): 1145-1153, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23937704

RESUMEN

OBJECTIVE: To evaluate the risk factors related to worsening of physical disabilities after treatment discharge among patients with leprosy administered 12 consecutive monthly doses of multidrug therapy (MDT/WHO). METHODS: Cohort study was carried out at the Leprosy Laboratory in Rio de Janeiro, Brazil. We evaluated patients with multibacillary leprosy treated (MDT/WHO) between 1997 and 2007. The Cox proportional hazards model was used to estimate the relationship between the onset of physical disabilities after release from treatment and epidemiological and clinical characteristics. RESULTS: The total observation time period for the 368 patients was 1 570 person-years (PY), averaging 4.3 years per patient. The overall incidence rate of worsening of disability was 6.5/100 PY. Among those who began treatment with no disability, the incidence rate of physical disability was 4.5/100 PY. Among those who started treatment with Grade 1 or 2 disabilities, the incidence rate of deterioration was 10.5/100 PY. The survival analysis evidenced that when disability grade was 1, the risk was 1.61 (95% CI: 1.02-2.56), when disability was 2, the risk was 2.37 (95% CI 1.35-4.16), and when the number of skin lesions was 15 or more, an HR = 1.97 (95% CI: 1.07-3.63). Patients with neuritis showed a 65% increased risk of worsening of disability (HR = 1.65 [95% CI: 1.08-2.52]). CONCLUSION: Impairment at diagnosis was the main risk factor for neurological worsening after treatment/MDT. Early diagnosis and prompt treatment of reactional episodes remain the main means of preventing physical disabilities.


Asunto(s)
Evaluación de la Discapacidad , Progresión de la Enfermedad , Leprostáticos/uso terapéutico , Lepra Multibacilar/complicaciones , Enfermedades del Sistema Nervioso/etiología , Adolescente , Adulto , Anciano , Instituciones de Atención Ambulatoria , Brasil , Niño , Preescolar , Estudios de Cohortes , Personas con Discapacidad , Quimioterapia Combinada , Femenino , Humanos , Leprostáticos/administración & dosificación , Leprostáticos/efectos adversos , Lepra Multibacilar/tratamiento farmacológico , Lepra Multibacilar/patología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/complicaciones , Alta del Paciente , Modelos de Riesgos Proporcionales , Factores de Riesgo , Adulto Joven
7.
J Trop Med ; 2013: 596316, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23690793

RESUMEN

A broad variety of factors have been associated with leprosy among contacts, including socioeconomic, epidemiological, and genetic characteristics. Data from 7,174 contacts of leprosy patients from a leprosy outpatient clinic in Rio de Janeiro, Brazil, 1987-2010, were analyzed to investigate the effects of kinship, individual, and contextual factors on leprosy. Multivariate analyses were performed using a robust estimation method. In the prevalence analysis, close kinship (sibling OR = 2.75, offspring OR = 2.00, and other relatives OR = 1.70), socioeconomic factors, and the duration of exposure to the bacillus were associated to leprosy. In the incidence analysis, significant risks were found for all categories of kinship (parents RR = 10.93, spouse, boyfriend/girlfriend, and bride/groom RR = 7.53, sibling RR = 7.03, offspring RR = 5.34, and other relatives RR = 3.71). Once the treatment of the index case was initiated, other factors lost their significance, and the index case bacteriological index and BCG (Bacillus Calmette-Guérin vaccine) protection had a greater impact. Our findings suggested that both genetic susceptibility and physical exposure play an important role in the epidemiology of leprosy, but it was not possible establishing the role of genetic factor. Analyses of other factors related to the genotype of individuals, such as genetic polymorphisms, are needed.

8.
Mem. Inst. Oswaldo Cruz ; 107(8): 1054-1059, Dec. 2012. graf, tab
Artículo en Inglés | LILACS | ID: lil-660655

RESUMEN

Contact surveillance is a valuable strategy for controlling leprosy. A dynamic cohort study of leprosy contacts was initiated in 1987 at Oswaldo Cruz Foundation. The objective of this work was to review the data on the major risk factors leading up to the infectious stage of the disease, estimate incidence rates of leprosy in the cohort and characterise the risk factors for the disease among the contacts under surveillance. The incidence rate of leprosy among contacts of leprosy patients was estimated at 0.01694 cases per person-year in the first five years of follow-up. The following factors were associated with acquiring the disease: (i) not receiving the BCG vaccine, (ii) a negative Mitsuda reaction and (iii) contact with a patient with a multibacillary clinical form of leprosy. The contacts of index patients who had high bacilloscopic index scores > 1 were at especially high risk of infection. The following factors were associated with infection, which was defined as a seropositive reaction for anti-phenolic glicolipid-1 IgM: (i) young age (< 20 years), (ii) a low measured Mitsuda reaction (< 5 mm) and (iii) contact with an index patient who had a high bacilloscopic index. BCG vaccination and re-vaccination were shown to be protective among household contacts. The main conclusions of this study indicate an urgent need for additional leprosy control strategies in areas with a high incidence of the disease.


Asunto(s)
Humanos , Trazado de Contacto/estadística & datos numéricos , Lepra/transmisión , Estudios de Cohortes , Composición Familiar , Incidencia , Lepra/epidemiología , Lepra/prevención & control , Modelos Biológicos , Vigilancia de la Población , Factores de Tiempo
9.
Mem Inst Oswaldo Cruz ; 107(2): 246-53, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22415265

RESUMEN

Nerve biopsy examination is an important auxiliary procedure for diagnosing pure neural leprosy (PNL). When acid-fast bacilli (AFB) are not detected in the nerve sample, the value of other nonspecific histological alterations should be considered along with pertinent clinical, electroneuromyographical and laboratory data (the detection of Mycobacterium leprae DNA with polymerase chain reaction and the detection of serum anti-phenolic glycolipid 1 antibodies) to support a possible or probable PNL diagnosis. Three hundred forty nerve samples [144 from PNL patients and 196 from patients with non-leprosy peripheral neuropathies (NLN)] were examined. Both AFB-negative and AFB-positive PNL samples had more frequent histopathological alterations (epithelioid granulomas, mononuclear infiltrates, fibrosis, perineurial and subperineurial oedema and decreased numbers of myelinated fibres) than the NLN group. Multivariate analysis revealed that independently, mononuclear infiltrate and perineurial fibrosis were more common in the PNL group and were able to correctly classify AFB-negative PNL samples. These results indicate that even in the absence of AFB, these histopathological nerve alterations may justify a PNL diagnosis when observed in conjunction with pertinent clinical, epidemiological and laboratory data.


Asunto(s)
Lepra Tuberculoide/patología , Nervios Periféricos/patología , Biopsia , Estudios de Casos y Controles , Humanos
10.
Mem. Inst. Oswaldo Cruz ; 107(2): 246-253, Mar. 2012. ilus, tab
Artículo en Inglés | LILACS | ID: lil-617072

RESUMEN

Nerve biopsy examination is an important auxiliary procedure for diagnosing pure neural leprosy (PNL). When acid-fast bacilli (AFB) are not detected in the nerve sample, the value of other nonspecific histological alterations should be considered along with pertinent clinical, electroneuromyographical and laboratory data (the detection of Mycobacterium leprae DNA with polymerase chain reaction and the detection of serum anti-phenolic glycolipid 1 antibodies) to support a possible or probable PNL diagnosis. Three hundred forty nerve samples [144 from PNL patients and 196 from patients with non-leprosy peripheral neuropathies (NLN)] were examined. Both AFB-negative and AFB-positive PNL samples had more frequent histopathological alterations (epithelioid granulomas, mononuclear infiltrates, fibrosis, perineurial and subperineurial oedema and decreased numbers of myelinated fibres) than the NLN group. Multivariate analysis revealed that independently, mononuclear infiltrate and perineurial fibrosis were more common in the PNL group and were able to correctly classify AFB-negative PNL samples. These results indicate that even in the absence of AFB, these histopathological nerve alterations may justify a PNL diagnosis when observed in conjunction with pertinent clinical, epidemiological and laboratory data.


Asunto(s)
Humanos , Lepra Tuberculoide/patología , Nervios Periféricos/patología , Biopsia , Estudios de Casos y Controles
11.
Mem Inst Oswaldo Cruz ; 107(8): 1054-9, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23295758

RESUMEN

Contact surveillance is a valuable strategy for controlling leprosy. A dynamic cohort study of leprosy contacts was initiated in 1987 at Oswaldo Cruz Foundation. The objective of this work was to review the data on the major risk factors leading up to the infectious stage of the disease, estimate incidence rates of leprosy in the cohort and characterise the risk factors for the disease among the contacts under surveillance. The incidence rate of leprosy among contacts of leprosy patients was estimated at 0.01694 cases per person-year in the first five years of follow-up. The following factors were associated with acquiring the disease: (i) not receiving the BCG vaccine, (ii) a negative Mitsuda reaction and (iii) contact with a patient with a multibacillary clinical form of leprosy. The contacts of index patients who had high bacilloscopic index scores > 1 were at especially high risk of infection. The following factors were associated with infection, which was defined as a seropositive reaction for anti-phenolic glicolipid-1 IgM: (i) young age (< 20 years), (ii) a low measured Mitsuda reaction (< 5 mm) and (iii) contact with an index patient who had a high bacilloscopic index. BCG vaccination and re-vaccination were shown to be protective among household contacts. The main conclusions of this study indicate an urgent need for additional leprosy control strategies in areas with a high incidence of the disease.


Asunto(s)
Trazado de Contacto/estadística & datos numéricos , Lepra/transmisión , Estudios de Cohortes , Composición Familiar , Humanos , Incidencia , Lepra/epidemiología , Lepra/prevención & control , Modelos Biológicos , Vigilancia de la Población , Factores de Tiempo
12.
BMC Infect Dis ; 11: 339, 2011 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-22166091

RESUMEN

BACKGROUND: Caused by Mycobacterium leprae (ML), leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I) plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems. METHODS: In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT), borderline lepromatous (NR BL), and lepromatous (NR LL) leprosy patients in addition to healthy controls (HC). LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α) were evaluated at diagnosis and during development of reversal (RR) or erythema nodosum leprosum (ENL) reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method. RESULTS: The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients) in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients). Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients. Interestingly, IGF-I behaved contrary to what was observed during RR episodes in R BL patients. CONCLUSIONS: Our data revealed important alterations in the IGF system in relation to the status of the host immune-inflammatory response to ML while at the same time pointing to the circulating IGF-I/IGFBP-3 levels as possible predictive biomarkers for ENL in LL patients at diagnosis.


Asunto(s)
Biomarcadores/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Lepra/patología , Lepra/fisiopatología , Adulto , Anciano , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Lepra/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Suero/química , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangre
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