Sandra Maria Barbosa Durães

TNF -308G>A Single Nucleotide Polymorphism Is Associated With Leprosy Among Brazilians: A Genetic Epidemiology Assessment, Meta-Analysis, and Functional Study

Leprosy is an infectious disease caused by Mycobacterium leprae. Tumor necrosis factor (TNF) plays a key role in the host response. Some association studies have implicated the single nucleotide polymorphism TNF -308G>A in leprosy susceptibility, but these results are still controversial. We first conducted 4 association studies (2639 individuals) that showed a protective effect of the -308A allele (odds ratio [OR] = 0.77; P = .005). Next, results of a meta-analysis reinforced this association after inclusion of our new data (OR = 0.74; P = .04). Furthermore, a subgroup analysis including only Brazilian studies suggested that the association is specific to this population (OR = 0.63; P = .005). Finally, functional analyses using whole blood cultures showed that patients carrying the -308A allele produced higher TNF levels after lipopolysaccharide (LPS) (6 hours) and M. leprae (3 hours) stimulation. These results reinforce the association between TNF and leprosy and suggest the -308A allele as a marker of disease resistance, especially among Brazilians.

Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil

BACKGROUNDS ultibacillary patients are the major source of infection in leprosy. Nevertheless, the risk is higher in household contacts between multibacillary patients than paucibacillary patients and in the general population. Household contacts are in close genetic relationship with the index case-patient. OBJECTIVE To evaluate epidemiological data of the following variables: age, gender, education level, genetic proximity, and type of contact with the index case-patient (household or not) in 107 families with leprosy. METHODS Home visits were conducted to clinically examine family members. The medical charts of index case-patients and co-prevalent cases were reviewed. RESULTS The controlled analysis of variables such as type of contact and genetic proximity revealed that household contacts and first-degree kinship are independently associated with a higher chance of contracting the disease. CONCLUSION Household contacts are often genetically closer to the index case-patient. To investigate the independent relevance of these risks in leprosy surveillance contact studies has been a challenge. Our results confirm literature data that show the influence of genetics in the susceptibility to leprosy per se.

Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy

Mycobacterium leprae infects macrophages and Schwann cells inducing a gene expression program to facilitate its replication and progression to disease. MicroRNAs (miRNAs) are key regulators of gene expression and could be involved during the infection. To address the genetic influence of miRNAs in leprosy, we enrolled 1,098 individuals and conducted a case-control analysis in order to study four miRNAs genes containing single nucleotide polymorphism (miRSNP). We tested miRSNP-125a (rs12975333 G>T), miRSNP-223 (rs34952329 *>T), miRSNP-196a-2 (rs11614913 C>T) and miRSNP-146a (rs2910164 G>C). Amongst them, miRSNP-146a was the unique gene associated with risk to leprosy per se (GC OR = 1.44, p = 0.04; CC OR = 2.18, p = 0.0091). We replicated this finding showing that the C-allele was over-transmitted (p = 0.003) using a transmission-disequilibrium test. A functional analysis revealed that live M. leprae (MOI 100∶1) was able to induce miR-146a expression in THP-1 (p<0.05). Furthermore, pure neural leprosy biopsies expressed augmented levels of that miRNA as compared to biopsy samples from neuropathies not related with leprosy (p = 0.001). Interestingly, carriers of the risk variant (C-allele) produce higher levels of mature miR-146a in nerves (p = 0.04). From skin biopsies, although we observed augmented levels of miR-146a, we were not able to correlate it with a particular clinical form or neither host genotype. MiR-146a is known to modulate TNF levels, thus we assessed TNF expression (nerve biopsies) and released by peripheral blood mononuclear cells infected with BCG Moreau. In both cases lower TNF levels correlates with subjects carrying the risk C-allele, (p = 0.0453 and p = 0.0352; respectively), which is consistent with an immunomodulatory role of this miRNA in leprosy.

The psychiatric facet of hyperhidrosis: demographics, disability, quality of life, and associated psychopathology.

We compared the sociodemographic and psychiatric features of treatment-seeking patients with (n=17) and without (n=29) primary hyperhidrosis (HYH) attending an outpatient dermatological clinic. Subjects were assessed with a structured clinical questionnaire, the Mini International Neuropsychiatric Interview, as well as the Screening for Abnormal Olfactory Experiences (to assess for symptoms of olfactory reference syndrome), the Obsessive-Compulsive Inventory-Revised, the Social Phobia Inventory, the Beck Depression and Anxiety Inventories, the Skindex-16 (a quality of life measure for patients with skin diseases), and the Sheehan Disability Scale. Patients with HYH were more frequently younger (p=0.003), unmarried (p=0.004), employed (p=0.019), more educated (p<0.0001), and better paid (p=0.001) than non-HYH patients. However, they also reported greater disabilities and impairments in work/school (p=0.05) and social life (p=0.014) domains, worse quality of life in emotional (p=0.003) and functioning (p>0.001) dimensions, and they had a greater frequency of comorbid social anxiety disorder (p=0.019). Conversely, non-HYH patients had greater severity of obsessive-compulsive neutralization symptoms (repeating compulsions, counting, and having lucky/unlucky numbers) (p=0.034). In conclusion, patients with HYH are characterized by differential sociodemographic and psychopathological characteristics, with major disability, marked impairment in quality of life, and increased rates of social anxiety disorder. (Journal of Psychiatric Practice 2014;20:316–323)

Positividade sorológica antiPGL-I em contatos domiciliares e peridomiciliares de hanseníase em área urbana

BACKGROUND: Actually many studies have been made to evaluate the predictive value of tests that identify patients infected by Mycobacterium leprae. Among then, the serology that determinates the presence o M. leprae specific antibody. OBJECTIVES: To know the infections tax among households and direct neighbours contacts, establish soropositivity relationship according to sex, household/ neighbour, age and classification of leprosy of the index case (paucibacillary x multibacillary). PATIENTS AND METHODS: seroepidemiological study covering all the household and neighbours of leprosy patients diagnosticated from 1998 to 2002, in the second district of Duque de Caxias, Rio de Janeiro, using fast ML-Flow. RESULTS: A total of 2.130 contacts were identified in 390 domiciles of leprosy patients. Of the 2130 contacts, 1866 were submmited to serology (12.4% lost). Seroprevalence was 15,7%(292/1866); 15.8% household and 15.6% neighbour. The relationship of seropositivity with sex and age (>15 >15 years old) did not shown any statistic difference. But it was seen among contacts of MB index cases ( 67,5%) 2 times higher than contacts of PB cases (32,5%). DISCUSSION / CONCLUSION: In highly endemic areas for leprosy, situated at peripheral metropoliten cities not only household contacts of the index case, but also people living in the close vicinity were more likely to harbour antibodies against M. leprae. Through measuring the serological status of contacts and using a broader definition for them, higher risk groups can be more specifically identified.

Leprosy late-onset neuropathy: an uncommon presentation of leprosy

Clinical and pathological findings in leprosy are determined by the natural host immune response to Mycobacterium leprae. We previously described cases of painful neuropathy (PN) with no concurrent cause apart from a past history of leprosy successfully treated. Four leprosy previously treated patients who developed a PN years after multidrug therapy (MDT) are reported. The mean patient age was 52.75 years (47-64). The mean time interval of the recent neuropathy from the previous MDT was 19 years (12-26). A painful multiplex neuritis or polyneuropathy were observed respectively in two cases. Electrophysiological studies disclosed a sensory axonal neuropathy in two cases. Microvasculitis with no bacilli was seen in nerve biopsy. Neuropathic symptoms were improved with prednisone. We consider these cases as being a leprosy late-onset neuropathy (LLON) form of presentation. A delayed immune reaction could explain the late appearance of LLON.

Association of IL10 Polymorphisms and Leprosy: A Meta-Analysis

Leprosy is a chronic infectious disease that depends on the interplay of several factors. Single nucleotide polymorphisms (SNPs) in host immune related genes have been consistently suggested as participants in susceptibility towards disease. Interleukin-10 (IL-10) is a crucial immunomodulatory cytokine in mycobacterial pathogenesis and especially the -819C>T SNP (rs1800871) has been tested in several case-control studies indicating association with leprosy risk, although a recent consensus estimate is still missing. In this study, we evaluated the association of the -819C>T SNP and leprosy in two new Brazilian family-based populations. Then, we performed meta-analysis for this polymorphism summarizing published studies including these Brazilian family-based groups. Finally, we also retrieved published studies for other distal and proximal IL10 polymorphisms: -3575 T>A (rs1800890), -2849 G>A (rs6703630), -2763 C>A (rs6693899), -1082 G>A (rs1800896) and -592 C>A (rs1800872). Results from meta-analysis supported a significant susceptibility association for the -819T allele, with pooled Odds Ratio of 1.22 (CI = 1.11–1.34) and P-value = 3x10–5 confirming previous data. This result remained unaltered after inclusion of the Brazilian family-based groups (OR = 1.2, CI = 1.10–1.31, P-value = 2x10–5). Also, meta-analysis confirmed association of -592 A allele and leprosy outcome (OR = 1.24, CI = 1.03–1.50, P-value = 0.02). In support of this, linkage disequilibrium analysis in 1000 genomes AFR, EUR, ASN and AMR populations pointed to r2 = 1.0 between the -592C>A and -819C>T SNPs. We found no evidence of association for the other IL10 polymorphisms analyzed for leprosy outcome. Our results reinforce the role of the -819C>T as a tag SNP (rs1800871) and its association with leprosy susceptibility.

Síndrome stiff skin: relato de caso

Sindrome stiff skin e doenca rara, esclerodermiforme, de etiologia desconhecida, caracterizada por endurecimento petreo da pele, hipertricose leve e limitacao da mobilidade articular. Nao ha tratamento efetivo ate o momento. Exercicios e reabilitacao sao importantes para manter a qualidade de vida do paciente. Os autores apresentam caso de um menino de dois anos de idade com endurecimento cutâneo progressivo desde os oito meses de idade e restricao secundaria da mobilidade articular, diagnosticado como Sindrome stiff skin

PARACOCCIDIOIDOMYCOSIS IN A RENAL TRANSPLANT RECIPIENT

Paracoccidioidomycosis (PCM) is the most common endemic mycosis in Latin America. The etiological agents, which comprise two species, Paracoccidioides brasiliensis and P. lutzii, are thermodimorphic fungi that usually affect previously healthy adults. They primarily involve the lungs and then disseminate to other organs. Such mycosis is rare in organ transplant recipients; there have been only three cases reported in literature, until now. We report a case of PCM in a renal transplant recipient with an unusual dermatological presentation.

Scleredema of Buschke associated with difficult-to-control type 2 diabetes mellitus

Scleredema of Buschke (SB) is a rare disorder of connective tissue characterized by diffuse non-pitting induration of the skin, mainly on the cervical, deltoid and dorsal regions. It is a cutaneous mucinosis of unknown etiology and is associated with bacterial or viral infections, hematological disorders and diabetes mellitus. Histopathological examination shows thickened dermis with wide collagen bundles separated by gaps that correspond to mucopolysaccharide deposits, visualized using special staining. Several treatments are reported in the literature without well-established results. We report a case of SB in a patient with type 2 diabetes mellitus.