Haroldo José de Matos

Role of Tumor Necrosis Factor–α and Interleukin-10 Promoter Gene Polymorphisms in Leprosy

Single-nucleotide polymorphismswithin thegenescodingfortumornecrosisfactor(TNF)‐a and interleukin (IL)‐10 have been associated with several infectious diseases. To determine whether such polymorphisms are associated with leprosy, genotyping was performed at the 308 and 238 positions of the promoter of the TNF-a gene in 210 and 191 patients with multibacillary (MB) leprosy, respectively; 90 and 79 patients with paucibacillary (PB) leprosy; and 92 control subjects. For the 592 and 819 positions within the promoter of the IL-10 gene, 143 patients with MB leprosy, 79 patients with PB leprosy, and 62 control subjects were included in the analysis. TNF2 allele frequency was significantly higheramong controlsubjects than among all patients with leprosy or in the MB group ( and ). For the ILP ! .05 P ! .01 10 gene, the frequency of the homozygous 819TT genotype was significantly higher among patients than among control subjects. These data indicate that a relationship exists between TNF-a and IL-10 promoter polymorphisms and the development of PB leprosy. The more benign paucibacillary (PB) forms of leprosy— borderline tuberculoid (BT) and tuberculoid tuberculoid (TT) leprosy—are characterized by the predominance of a Th1-type immune response, the presence of well-formed granulomas at the site of the lesion, and control of mycobacterial replication. In contrast, in the multibacillary (MB) forms—borderline borderline (BB) and borderline lepromatous (BL) leprosy and lepromatous leprosy (LL)—no granuloma is seen, and high bacterial load and antibody levels are detected. Cytokines evidently play a critical role in triggering host-pathogen interactions. On one hand, greater tumor necrosis factor (TNF)–a production,

Ponto de corte do índice Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) avaliado pela curva Receiver Operating Characteristic (ROC) na detecção de síndrome metabólica em crianças pré-púberes com excesso de peso

OBJECTIVE: To establish, among the cut-off values for the homeostatic model assessment for insulin resistance index (HOMA-IR) cited in the literature, the best in identifying metabolic syndrome (MS) in obese and overweight children. METHODS: A total of 106 pre-pubertal children were studied. The definition of MS was adapted from that of the International Diabetes Federation. For each cut-off values for HOMA-IR, it was estimated sensibility and specificity for MS. A receiver operating characteristic (ROC) curve was generated using these values. RESULTS: The study included 106 obese (37 girls and 69 boys) and 34 overweight (19 girls and 15 boys) children aged 6,5 ± 2,3 years. The accuracy of the ROC curve was 72%, and the best cut-off value for HOMAIR was 2,5, with sensitivity of 61% and specificity of 74%. CONCLUSIONS: HOMA-IR may be useful to detect MS and the cut-off 2,5 seems to be the best in obese and overweight pre-pubertal children.

Identification of specific proteins and peptides in Mycobacterium leprae suitable for the selective diagnosis of leprosy

Diagnosis of leprosy is a major obstacle to disease control and has been compromised in the past due to the lack of specific reagents. We have used comparative genome analysis to identify genes that are specific to Mycobacterium leprae and tested both recombinant proteins and synthetic peptides from a subset of these for immunological reactivity. Four unique recombinant proteins (ML0008, ML0126, ML1057, and ML2567) and a panel of 58 peptides (15 and 9 mer) were tested for IFN-γ responses in PBMC from leprosy patients and contacts, tuberculosis patients, and endemic and nonendemic controls. The responses to the four recombinant proteins gave higher levels of IFN-γ production, but less specificity, than the peptides. Thirty-five peptides showed IFN-γ responses only in the paucibacillary leprosy and household contact groups, with no responses in the tuberculosis or endemic control groups. High frequencies of IFN-γ-producing CD4+ and CD8+ T cells specific for the 15- and 9-mer peptides were observed in the blood of a paucibacillary leprosy patient. 9-mer peptides preferentially activated CD8+ T cells, while the 15-mer peptides were efficient in inducing responses in both the CD4+ and CD8+ T cell subsets. Four of the six 9-mer peptides tested showed promising specificity, indicating that CD8+ T cell epitopes may also have diagnostic potential. Those peptides that provide specific responses in leprosy patients from an endemic setting could potentially be developed into a rapid diagnostic test for the early detection of M. leprae infection and epidemiological surveys of the incidence of leprosy, of which little is known.

Os indicadores da hanseníase e as estratégias de eliminação da doença, em município endêmico do Estado do Rio de Janeiro, Brasil

Various strategies for eliminating leprosy as a public health problem have evolved in the last 20 years. In some countries, especially highly endemic ones, the WHO target rate for leprosy elimination fell far short. The current study aimed to analyze the impact of different strategies for reducing leprosy prevalence in Duque de Caxias, a highly endemic municipality in Rio de Janeiro State, Brazil. The study observed the evolution of traditional operational indicators for the disease and their trends in the last 14 years. The indicators were calculated using the National Communicable Diseases Database (SINAN). Strategies that focused on decentralization of patient care and/or localized campaigns were associated with earlier case detection, reduction in prevalence, and shorter patient time in the active registry. An increase in the annual detection rate could be related to the existence of hidden prevalence or individuals with asymptomatic infection. New complementary strategies are needed to eliminate the disease in Duque de Caxias.

REACTIONAL STATES IN MULTIBACILLARY HANSEN DISEASE PATIENTS DURING MULTIDRUG THERAPY

It is well known that reactions are commonplace occurrences during the course of leprosy disease. Stigmatization may even be attributable to reactions which are also responsible for the worsening of neural lesions. A cohort of 162 newly-diagnosed baciloscopically positive patients from the Leprosy Care Outpatient Clinic of the Oswaldo Cruz Foundation (FIOCRUZ) was selected for this study. While 46% of the multibacillary (MB) patients submitted to the 24 fixed-dose multidrug therapy (MDT) regimen suffered reactions during treatment, it was found that all MBs were susceptible and that constant attention and care were required at all times. Fourteen per cent were classified as BB, 52% as BL, and 33% as LL. None of the variables under study, such as, sex, age, clinical form, length of illness, length of dermatological lesions, baciloscopic index (BI), or degree of disability proved to be associate with reaction among the patients studied. Reversal Reaction (RR) occurred in 45%, and Erythema Nodosum Leprosum (ENL) occurred in 55%. Among BB patients who developed reactions (15 patients), 93% presented RR; while among the LL patients who developed reactions (34 patients), 91% presented ENL. Likewise, ENL was very frequent among those with disseminate lesions, while RR was most often observed in patients with segmentary lesions. RR was also most likely to occur during the initial months of treatment. It was demonstrated that the recurrence rate of ENL was significantly higher than that of RR. Neither grade of disability nor BI was shown to be associated with RR and ENL reaction. However, the RR rate was significantly higher among patients showing BI < 3, while ENL predominated among those patients with BI > 3.

Epidemiologia da hanseníase em coorte de contatos intradomiciliares no Rio de Janeiro (1987-1991)

This study aimed to identify factors influencing the development of leprosy (Hansens disease) in household contacts. A dynamic cohort was analyzed from 1987 to 1991 at the Hansens Disease Department of the Oswaldo Cruz Foundation in Rio de Janeiro. The incidence rate was 0.01694 person-years of follow-up. Nevertheless, for subjects at the end of the first year of follow-up the incidence rate was 0.06385 (end of second year, 0.03299; end of third year, 0.02370; end of fourth year, 0.018622; and end of observation period, 0.01694). A stepwise multivariate logistic regression model was proposed to study the risk of developing leprosy, including co-prevalent cases, totaling 758 contacts. In the final model, the risk was associated with a negative Mitsuda skin test (OR = 3.093; CI 95% = 1.735-5.514), prior BCG vaccination (OR = 0.3802; CI 95% = 0.2151-0.66719), and multibacillary primary clinical form (OR = 2.547; CI 95% = 1.249-5.192). The results showed that both multibacillary leprosy and specific immune status are significant indicators for developing the disease in a cohort of household contacts.

Aspectos epidemiológicos da hanseníase: uma abordagem espacial

The objective of this study was to identify spatial patterns in the occurrence of leprosy in Duque de Caxias, a municipality (county) with high endemicity for the disease in the State of Rio de Janeiro, Brazil. The authors selected all new leprosy cases reported to the Brazilian National Database on Diseases of Notification (SINAN) from 1998 to 2006. The analysis was performed according to three-year periods, followed by spatial analysis according to the local empirical Bayesian method and calculation of global (Moran) and local (LISA) spatial autocorrelation. The analysis showed marked improvement in the epidemiological situation associated with earlier diagnosis. There was a reduction in the proportion of cases with grade II leprosy, from 13.6% to 8.6% (p = 0.04), and increased detection of cases with the indeterminate form, from 10.3% to 18% (p = 0.00). Spatial analysis identified a cluster in the South-Northwest of the municipality, not directly related to the actions or decentralization campaign, proving to be an important tool for identifying critical areas for the endemic and assessing the impact of strategic measures to combat the disease.

Trends in a Cohort of HIV-infected pregnant women in Rio de Janeiro, 1996-2004

OBJECTIVE: To describe trends in sociodemographic, immunological and virological profiles and interventions to decrease the risk of mother-to-child HIV transmission. METHODS: Retrospective cohort study conducted at a tertiary institution in Rio de Janeiro, Brazil from January 1996 to December 2004. Analysis was performed by stratification in three time periods: 1996-1998 (P1), 1999-2001 (P2) and 2002-2004 (P3). RESULTS: In 9 years, 622 pregnancies occurred. Complications included: maternal mortality 0.3%, stillbirths 2.5%, miscarriages 0.6%, neonatal mortality 1.1%, prematurity 9.9%, low birth weight (LBW) 16.5%, congenital malformations 2.2%. The number of HIV-infected pregnant patients grew threefold over time reflecting increased prevalence of disease and patient identification. HIV diagnosis before pregnancy increased from 30% in P1 to 45% in P3. The proportion of pregnant women receiving highly active antiretroviral therapy increased from none (P1) to 88% (P3) with a significant trend towards women delivering at undetectable viral loads in later years despite a higher frequency of advanced disease. Scheduled cesarean deliveries increased from 35% in P1 to 48% in P3. Perinatal transmission rates were 2.4% with a decline from 3.5% in P1 to 1.6% in P3. Neonatal outcomes tended to remain constant or improve with time. A slight rise in LBW and congenital malformations were observed. CONCLUSIONS: During the observational period, HIV+ pregnant women presented with more advanced disease and lower socio-economic status. However, improved management of HIV-infected patients (associated with increased identification and increased availability of treatment) resulted into very low transmission rates similar to those of developed countries with overall improvement of patient outcomes.

HLA markers in familial Lichen Sclerosus

Background: Lichen sclerosus (LS) has been identified with increased frequency in families,often associated with HLA markers, mainly DQ7. A genetic co‐etiology seems likely in this setting. Moreover, there is an association of LS with autoimmune disorders, such as the presence of anti‐thyroid peroxidase autoantibodies (anti‐TPO), a hallmark of autoimmune thyroid diseases.

Single nucleotide polymorphisms (SNPs) at -238 and -308 positions in the TNFα promoter: Clinical and bacteriological evaluation in leprosy

Tumor necrosis factor alpha (TNFalpha) plays a key role in orchestrating the complex events involved in inflammation and immune response. The presence of single nucleotide polymorphisms (SNPs) within the promoter region of the TNFa gene has been associated with a number of diseases. The aim of this study was to investigate the distribution of polymorphisms at positions -238 (G/A) and -308 (G/A) at the TNFalpha promoter, and its association to the outcome of different clinical forms of leprosy. Furthermore, the bacteriological index (BI) was evaluated among genotyped multibacillary (MB) patients in order to investigate the possible influence of each polymorphism on the bacterial load. This study included a total of 631 leprosy patients being 401 MB and 230 paucibacillary (PB), that was further separated according to its ethnicity (Afro- and Euro-Brazilians). The combination of SNPs in haplotypes generated three different arrangements: TNFG-G, TNFG-A and TNFA-G. In spite of the marked differences observed in the frequency of the haplotypes along the ethnic groups, no statistical differences were observed in haplotype frequencies between MB and PB patients. The BI analyses showed a lower bacteriological index among the -308 carriers, while the BI of the -238 carriers was higher. Although no significance has been achieved in this analysis regarding the influence of the polymorphisms to the development of the clinical outcome, it seems that in a different stage (among the MB patients) the polymorphisms could contribute to the degree of severity observed.