Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection.

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.

Baixo conhecimento de doadores de sangue sobre a hanseníase como fator de vulnerabilidade para a disseminação da doença / Low knowledge of blood donors about leprosy as a vulnerability factor for the spread of the disease

Objetivo: caracterizar o doador de sangue e seu conhecimento sobre a hanseníase, visando contribuir para identificar pontos de vulnerabilidade sobre a doença. Metodologia: foram entrevistados doadores de sangue (n=199) através de um questionário estruturado abordando características socioeconômicas e o conhecimento sobre a hanseníase. Para a análise dos dados foi utilizado o método de Goodman e considerado significativo p<0,05. Resultados: dentre as perguntas sobre a hanseníase, a maioria dos participantes (65,83%) não tinha conhecimento da doença e nem o seu modo de transmissão (75,88%) e quando computado o conhecimento da Hanseníase, 1,51% conheciam, 39,70% conheciam pouco e 58,79% não conheciam a doença. Nossos resultados demonstraram que somente a escolaridade teve associação significativa com a falta de conhecimento sobre a hanseníase (p=0,0273). Conclusão: verificou-se déficit de conhecimento da população geral quanto à hanseníase. Sugerimos um aprimoramento da divulgação das informações quanto à doença a fim de promover melhoras nos serviços de saúde, acompanhamento dos doentes e prevenção da população saudável.

Objective: to characterize the blood donor and his knowledge about leprosy, aiming to contribute to identify vulnerability points about the disease. Methodology: blood donors (n=199) were interviewed through a structured questionnaire addressing socioeconomic characteristics and knowledge about leprosy. For the data analysis, the Goodman method was used and considered significant p<0.05. Results: Among the questions about leprosy, most participants (65.83%) did not know about the disease and its mode of transmission (75.88%) and when computing the knowledge of leprosy, 1.51% knew, 39,70% knew little and 58.79% did not know the disease. Our results showed that only schooling had a significant association with the lack of knowledge about leprosy (p=0,0273). Conclusion: there was a lack of knowledge of the general population regarding leprosy. We suggest an improved dissemination of information about the disease to promote improvements in health services, patient monitoring and prevention of the healthy population.

Asymptomatic Leprosy Infection among Blood Donors May Predict Disease Development and Suggests a Potential Mode of Transmission.

Blood donor samples (1,007) were assessed for anti-phenolic glycolipid 1 (PGL-1) IgM antibodies and Mycobacterium leprae DNA presence, which had 3.8% and 0.3% positivity, respectively. After a 5-year follow-up period, six individuals with positive markers developed leprosy, raising the hypothesis that asymptomatic infection among blood donors may be an undisclosed mode of leprosy transmission via transfusion.

Leprosy and hepatitis B coinfection in southern Brazil

To investigate the association of leprosy with hepatitis B virus (HBV) infection, as yet unknown for South Brazil, we assessed hepatitis B virus coinfection in 199 South Brazilian leprosy patients (119 lepromatous, 15 tuberculoid, 30 borderline, 12 undetermined and 23 unspecified) and in 681 matched blood donors by screening for the hepatitis B virus markers HBSAg and anti-HBc, using ELISA. Positive samples were retested and anti-HBc+ only samples were tested for the hepatitis B surface antibody (anti-HBs). There was a strong association between leprosy and hepatitis B virus infection (OR = 9.8, 95% CI = 6.4–14.7; p = 0.004·E−30), as well as an association between HBV infection and lepromatous leprosy, compared to other forms (OR = 2.4, 95% CI = 1.2–4.8; p = 0.017). We also found that confinement due to leprosy was associated with hepatitis B virus infection (OR = 3.9, 95% CI = 2.1–7.4; p = 0.015·E−3). Leprosy patients are susceptible to develop hepatitis B virus infection, especially lepromatous. Institutionalized patients, who probably present a stronger Th2 response, have higher risk of being exposed to hepatitis B virus. This clearly emphasizes the need for special care to leprosy patients in preventing hepatitis B virus coinfection in South Brazil.

Leprosy and hepatitis B coinfection in southern Brazil.

To investigate the association of leprosy with hepatitis B virus (HBV) infection, as yet unknown for South Brazil, we assessed hepatitis B virus coinfection in 199 South Brazilian leprosy patients (119 lepromatous, 15 tuberculoid, 30 borderline, 12 undetermined and 23 unspecified) and in 681 matched blood donors by screening for the hepatitis B virus markers HBSAg and anti-HBc, using ELISA. Positive samples were retested and anti-HBc+ only samples were tested for the hepatitis B surface antibody (anti-HBs). There was a strong association between leprosy and hepatitis B virus infection (OR=9.8, 95% CI=6.4-14.7; p=0.004 · E(-30)), as well as an association between HBV infection and lepromatous leprosy, compared to other forms (OR=2.4, 95% CI=1.2-4.8; p=0.017). We also found that confinement due to leprosy was associated with hepatitis B virus infection (OR=3.9, 95% CI=2.1-7.4; p=0.015 · E(-3)). Leprosy patients are susceptible to develop hepatitis B virus infection, especially lepromatous. Institutionalized patients, who probably present a stronger Th2 response, have higher risk of being exposed to hepatitis B virus. This clearly emphasizes the need for special care to leprosy patients in preventing hepatitis B virus coinfection in South Brazil.

Brazilian blood donation eligibility criteria for dermatologic patients.

UNLABELLED: A focused and commented review on the impact of dermatologic diseases and interventions in the solidary act of donating blood is presented to dermatologists to better advise their patients. This is a review of current Brazilian technical regulations on hemotherapeutic procedures as determined by Ministerial Directive #1353/2011 by the Ministry of Health and current internal regulations of the Hemotherapy Center of Ribeirão Preto, a regional reference center in hemotherapeutic procedures. Criteria for permanent inaptitude: autoimmune diseases (>1 organ involved), personal history of cancer other than basal cell carcinoma, severe atopic dermatitis or psoriasis, pemphigus foliaceus, porphyrias, filariasis, leprosy, extra pulmonary tuberculosis or paracoccidioidomycosis, and previous use of etretinate. Drugs that impose temporary ineligibility: other systemic retinoids, systemic corticosteroids, 5-alpha-reductase inhibitors, vaccines, methotrexate, beta-blockers, minoxidil, anti-epileptic, and anti-psychotic drugs. Other conditions that impose temporary ineligibility: occupational accident with biologic material, piercing, tattoo, sexually transmitted diseases, herpes, and bacterial infections, among others. DISCUSSION: Thalidomide is currently missing in the teratogenic drugs list. Although finasteride was previously considered a drug that imposed permanent inaptitude, according to its short halflife current restriction of 1 month is still too long. Dermatologists should be able to advise their patients about proper timing to donate blood, and discuss the impact of drug withdrawal on treatment outcomes and to respect the designated washout periods.

Brazilian blood donation eligibility criteria for dermatologic patients / Critérios brasileiros de elegibilidade à doação de sangue para pacientes dermatológicos

A focused and commented review on the impact of dermatologic diseases and interventions in the solidary act of donating blood is presented to dermatologists to better advise their patients. This is a review of current Brazilian technical regulations on hemotherapeutic procedures as determined by Ministerial Directive #1353/2011 by the Ministry of Health and current internal regulations of the Hemotherapy Center of Ribeirão Preto, a regional reference center in hemotherapeutic procedures. Criteria for permanent inaptitude: autoimmune diseases (>1 organ involved), personal history of cancer other than basal cell carcinoma, severe atopic dermatitis or psoriasis, pemphigus foliaceus, porphyrias, filariasis, leprosy, extra pulmonary tuberculosis or paracoccidioidomycosis, and previous use of etretinate. Drugs that impose temporary ineligibility: other systemic retinoids, systemic corticosteroids, 5-alpha-reductase inhibitors, vaccines, methotrexate, beta-blockers, minoxidil, anti-epileptic, and anti-psychotic drugs. Other conditions that impose temporary ineligibility: occupational accident with biologic material, piercing, tattoo, sexually transmitted diseases, herpes, and bacterial infections, among others. Discussion: Thalidomide is currently missing in the teratogenic drugs list. Although finasteride was previously considered a drug that imposed permanent inaptitude, according to its short halflife current restriction of 1 month is still too long. Dermatologists should be able to advise their patients about proper timing to donate blood, and discuss the impact of drug withdrawal on treatment outcomes and to respect the designated washout periods.

Uma revisão centrada no impacto de doenças e intervenções dermatológicas no ato solidário de doar sangue é apresentada aos dermatologistas para melhor aconselhamento dos seus pacientes. Esta é uma revisão das atuais normas técnicas brasileiras sobre procedimentos hemoterápicos conforme determinado pela Portaria Ministerial no 1353/2011 do Ministério da Saúde e atuais normas internas do Hemocentro de Ribeirão Preto, um centro de referência regional em procedimentos hemoterápicos. Critérios para inaptidão definitiva: doenças autoimunes (>1 órgão comprometido), antecedente pessoal de câncer diferente de carcinoma basocelular, dermatite atópica ou psoríase graves, pênfigo foliáceo, porfirias, filariose, hanseníase, tuberculose ou paracoccidioidomicose extrapulmonares e uso prévio de etretinato. São condições de inelegibilidade temporária: uso de outros retinóides sistêmicos, corticoides sistêmicos, inibidores da 5-alfa-redutase, vacinas, metotrexato, betabloqueadores, minoxidil, anticonvulsivantes e antipsicóticos. Outras condições responsáveis por inaptidão temporária: acidente ocupacional com material biológico, "piercing", tatuagem, doenças sexualmente transmissíveis, herpes, infecções bacterianas, entre outras. Discussão: Talidomida atualmente não consta na lista de medicações teratogênicas. Apesar do uso da finasterida já ter sido considerada como critério para inaptidão definitiva, de acordo com sua meia-vida curta a restrição atual de 1 mês ainda é demasiadamente longa. Dermatologistas devem ser capazes de aconselhar seus pacientes sobre o momento adequado para doar sangue e discutir o impacto da suspensão de medicações nos resultados do tratamento de forma a respeitar os períodos de restrição designados.

Prevalence and genotypic distribution of hepatitis GB-C/HG and TT viruses in blood donors, mentally retarded children and four groups of patients in eastern Anatolia, Turkey.

We investigated the prevalence and genotypic distribution of GB virus-C/hepatitis G virus (GBV-C/HGV) and TT virus (TTV) in blood donors, mentally retarded children and four groups of patients living in Eastern Anatolia, Turkey. The prevalence and genetic analysis of TTV were determined by using the primers of the UTR and ORF1 regions of TTV, respectively. Reverse transcription nested (RT-n)-PCR was used to amplify 5' UTR of GBV-C/HGV. Genotyping of HGV was carried out by PCR-based genotyping assay while RFLP was conducted to determine the genotypes of TTV. TTV DNA was detected in 118 of 410 sera tested, giving an overall prevalence of 28.7%; GBV-C/HGV-RNA was detected in only 17 cases, giving an overall prevalence of 4.1%. No significant differences were observed in the number of positive or negative tests for GBV-C/HGV and TTV according to duration of illness or mean duration of institutionalization in any of the groups studied. Although all samples from the study population belonged to genotypes 1 and 4, the most common TTV genotype is G2. In conclusion, our results indicate a low endemicity of GBV-C/HGV and TTV infection in Eastern Anatolia, Turkey. The presence of G2 strains reveals the limited genetic diversity of the GBV-C/HGV circulating in Turkey. We suggest that TTV infection of genotypes 1 and 4 is prevalent in the same region.

Effect of HIV infection on the clinical spectrum of leprosy in Maiduguri.

The clinical features associated with different classes of leprosy patients co-infected with HIV in Maiduguri was studied and the classification of leprosy was done clinically and bacteriologically using Ridley-Jopling classification and bacteriological index respectively. The cases were classified as paucibacillary (Tuberculoid--TT and Borderline Tuberculoid--BTT) and multibacillary (Borderline Borderline--BB, Borderline Lepromatous BL and Lepromatous Leprosy--LL) leprosy. Eleven (10.5%) of 105 leprosy cases were HIV-seropositive comprising of 7 males and 4 females. Age range was 15 and 62 years. Among the HIV seropositive patients, those with paucibacillary (PB) leprosy were 6 (TT-1, BT-5) while multibacillary (MB) leprosy 5 (BB-1, BL-2, LL-2). The predominant clinical features were clawing of fingers (64%), ulcerations (64%), hand muscle atrophy (55%) and clawing of toes (45%). Some clinical features of paucibacillary leprosy such as sensory and hair losses (as is also seen in HIV negative patients) occurred in increased frequency in HIV positive patients belonging to the multibacillary class. The HIV infected leprosy patients are more likely to manifest advanced stages of the disease than the HIV seronegative patients.

Association between leprosy and HIV infection in Tanzania.

SETTING: An epidemiological study of the interaction of leprosy and HIV infection in Tanzania. OBJECTIVE: To establish the prevalence of HIV infection among leprosy patients, and to measure the association of HIV and leprosy by comparing the HIV prevalence in leprosy patients and blood donors. DESIGN: Testing for HIV infection in consecutively diagnosed leprosy patients (new and relapsed after MDT) in all regions in Tanzania successively for a period of 3 to 6 months during 1991, 1992 and 1993. RESULTS: Out of the total estimated eligible leprosy patients, 697 patients (69%) entered the final analysis. The HIV prevalence among these leprosy patients was 12% (83/697) as compared to 6% (8960/ 158,971) in blood donors examined in Tanzania during the same period. There were no significant differences in HIV seroprevalence by age, sex, residence or type of disease. However, the adjusted odds ratio (OR) of the presence of a BCG scar was 1.9 [95% confidence interval (CI) 1.1-3.3] among HIV-positive leprosy cases compared to HIV-negative leprosy cases. Comparing leprosy cases with blood donors as controls, the logistic regression model, controlling for sex, age group and residence, showed the OR for HIV seropositivity among leprosy patients to be 2.5 (95% CI 2.0-3.2). This association existed in all strata, but was strongest in the 15-34-year age group. No difference of HIV status between multibacillary and paucibacillary leprosy could be shown to exist. The point estimate of the population attributable risk of HIV infection for leprosy was 7%. CONCLUSION: HIV infection is associated with leprosy and might reverse the epidemiological trend of the slow decline in case notification in Tanzania if HIV infection is increasing greatly. Previous BCG vaccination loses its protection against leprosy in the presence of HIV infection. A repeated study is recommended in order to validate these findings, whereby recording of the disability grading of the cases is necessary to adjust for delay in diagnosis.

PIP: The association between HIV infection and leprosy was investigated in 731 consecutive leprosy cases from all 20 regions of Tanzania. These cases represented 69% of total notified new and relapsed leprosy cases reported in the 1991-93 study period. HIV prevalence among the 679 patients for whom complete data were available was 12% (83 cases). Leprosy patients aged 35-54 years and those without a BCG scar were significantly less likely than their counterparts aged 15-34 years and those with a BCG scar to be HIV-infected. There were no significant differences in HIV prevalence in terms of sex, urban or rural residence, new or relapsed cases, and paucibacillary or multibacillary leprosy. Among controls--all 158,971 blood donors tested for HIV during 1991 to 1993--HIV prevalence was 6%. The overall odds ratio for HIV infection among leprosy patients compared with controls, after adjustments for sex, age, and residence, was 2.5 (95% confidence interval, 2.0-3.2). Point estimates of the attributable risk and the population attributable risk were 57% and 7%, respectively. These findings indicate that HIV infection significantly increases the risk of leprosy in Tanzania and compromises the protective effect of BCG vaccination. Although case notifications of leprosy in Tanzania have not changed appreciably in the past 13 years, expansion of the HIV epidemic could have a significant effect on the epidemiology of leprosy.

Prevalence of HIV1 in leprosy patients in Rio de Janeiro, Brazil.

The purpose of this study was to learn if HIV1 infection was associated with leprosy in Rio de Janeiro, Brazil by comparing the prevalence rates of 1.016 leprosy patients tested on a voluntary basis and 78.482 blood donors. A cross-sectional survey of anti-HIV1 antibodies was conducted in Rio de Janeiro, from 1990 to 1992 for this purpose. HIV1 prevalence found among leprosy patients was (3 cases) 2.9 per 1000, and among blood donors was (282 cases) 3.8 per 1000. Such difference was not significant (OR = 0.79; p = 0.69). Since HIV1 cases were only found among male leprosy patients, further analysis excluded females. Male leprosy patients showed a slightly higher prevalence of HIV1 than blood donors before and after age adjustment. However, this result was not statistically significant (adjusted odds ratio = 1.38, 95% CI 0.35-4.5; p = 0.83). These data do not provide evidence that leprosy and HIV1 infection are associated in the State of Rio de Janeiro. This is consistent with similar investigations conducted elsewhere.

PIP: A cross-sectional study conducted in Rio de Janeiro, Brazil, in 1990-92 failed to document any association between HIV-1 infection and leprosy. Tested for antibodies to HIV were 1016 leprosy patients and 78,482 volunteer blood donors. The HIV prevalence was 2.9/1000 (3 cases) among leprosy patients and 3.8/1000 (282 cases) among blood donors (odds ratio, 0.79)--a nonsignificant difference. When standardized for age, these rates were 2.8/1000 and 2.9/1000, respectively. Since all 3 HIV cases in the leprosy group were men, the analysis was repeated to exclude females. Although male leprosy patients were 28% more likely to be HIV-infected than male blood donors (odds ratio, 0.79), the difference was, again, not significant. A similar lack of association has been reported in studies from other areas where both HIV and leprosy are prevalent. However, a large-scale nested case-control study in a cohort at high risk of HIV is necessary to more definitively reject this association.

Prevalência de HIV1 em pacientes de hanseníase no Rio de Janeiro, Brasil / Prevalence of HIV1 in leprosy patients in Rio de Janeiro, Brazil

A finalidade deste estudo foi a de saber se a infecçao pelo HIVl estaria associada à hanseníase no Rio de Janeiro, Brasil, comparando-se a taxa de prevalência de 1.016 pacientes de hanseníase testados de forma voluntária com 78.482 doadores de sangue. Com esta finalidade um estudo de prevalência de anticorpos anti-HIVl foi realizado no Rio de Janeiro de 1990 a 1992. A prevalência de HIVl em pacientes de hanseníase foi de 2,9 por 1.000 (3 casos) e entre os doadores de sangue a prevalêncía foi de 3,8 por 1.000 (282 casos ). Uma vez que os casos de HIVl entre pacientes de hanseníase se limitaram a homens, as pacientes femininas foram excluídas das análises posteriores. Pacientes de hanseníase do sexo masculino apresentaram um prevalência ligeiramente mais alta para o HIVl do que os doadores de sangue, antes e depois do ajuste por idade. Entretanto, este resultado nao foi estatisticamente significativo (RPC ajustado = 1,38, 95 por cento CI O,25-4,5 p = O,83). Estes resultados nao demonstram que hanseníase e a infecçao pelo HIVl estejam associados no Estado do Rio de Janeiro. Estes achados sao compatíveis com os resultados de investigaçoes semelhantes em outros centros.

Ultramicroelisa para la deteccion de anticuerpos IgM al Mycobacterium leprae utilizando muestras de sangre seca / Ultramicroelisa assay for the detection of IgM antibodies to Mycobacterium leprae using eluates of dried blood spots

En este trabajo se estebelecen las condiciones optimas para la deteccion de anticuerpos IgM al glicolipido fenolitico-I (GF-I) en muestras de sangre en papel de filtro utilizando el UltranicroELISA HANSEN y la tecnologia SUMA. Se estudiaron 30 doantes de sabgre y 58 pacientes leprosos. Para estas dos poblaciones se compararon los resultados de muestras de sangre seca colectadas en papel de filtro SS-2992 con los de suero, y se obtuvo una correlacion de 0.919 para doantes de sangre, 0.969 para pacientes y 0.954 para el total de las dos poblaciones....

The prevalence of human T-cell leukemia virus type I infection in patients with hematologic and nonhematologic diseases in an adult T-cell leukemia-endemic area of Japan.

In order to clarify the prevalence of human T-cell leukemia virus type I (HTLV-I) infection in the Kagoshima district, Japan, a highly endemic area for HTLV-I, antibodies for HTLV-I (anti-HTLV-I) were examined in the sera of 6167 from healthy residents and patients with various hematologic and nonhematologic diseases. In healthy residents, including blood donors, the prevalence of anti-HTLV-I was 11.9% (562/4741 persons). The prevalence increased with age, and was significantly higher in in females than in males (P less than 0.01). The prevalence of anti-HTLV-I in blood donors was 8.5%. In In hematologic diseases, the prevalence of anti-HTLV-I was 98.3% in ATL, 28.9% in lymphoproliferative disorders except ATL, and 10.6% in myeloproliferative disorders. In nonhematologic diseases, the prevalence of anti-HTLV-I was shown to be 29.5% in pulmonary tuberculosis, 25.8% in leprosy, 33.8% in chronic renal failure (CRF), 21.9% in autoimmune diseases, and 47.8% in strongyloidiasis. The various diseases except myeloproliferative disorders had significantly higher prevalence of anti-HTLV-I than healthy residents (P less than 0.01 or 0.05). For autoimmune diseases, the prevalence of anti-HTLV-I in patients with blood transfusion (55.6%) was higher than in those without blood transfusion (8.7%), and healthy residents. In hemodialysis patients with CRF who had received blood transfusions the prevalence of anti-HTLV-I increased with the number of blood transfusions. Therefore, HTLV-I transmission via blood transfusion would partially explain these high prevalence of anti-HTLV-I. However, the prevalence of anti-HTLV-I in hemodialysis patients with CRF was statistically higher than that in healthy residents, regardless of blood transfusion (P less than 0.01). Furthermore, hemodialysis patients showed significantly higher prevalence of anti-HTLV-I than healthy residents, even at a younger age. Patients with pulmonary tuberculosis and leprosy showed the same results as hemodialysis patients. These results suggest that possibility that HTLV-I infection has some relation not only to ATL but also to other diseases. Therefore, it seems very important to halt the spread of HTLV-I transmission as soon as possible.