Alterações da expressão da proteína PHEX na Hanseníase

A hanseníase é uma doença infecciosa causada pelo Mycobacteruim leprae, um bacilo intracelular obrigatório, que prolifera principalmente na pele e nos nervos periféricos no interior de células como macrófagos e células de Schwann. A transmissão ocorre por meio das mucosas das vias respiratórias, provavelmente por aerossóis expelidos por indivíduos infectados. O homem é o seu hospedeiro natural sendo a multiplicação do bacilo muito lenta, com um período de geração estimado de 14 dias. Apesar da mínima variação no genoma do M. leprae, a doença é caracterizada por um espectro de formas clínicas bem definido, decorrente da capacidade de resposta imune do hospedeiro. Em pacientes classificados como multibacilares (MB) a doença é disseminada, com inúmeras lesões de pele e proliferação bacilar considerável. Nesses indivíduos ocorre hiporresponsividade celular ao M. leprae. Nas formas paucibacilares (PB), os pacientes apresentam uma ou poucas lesões, a carga bacilar é pequena e, às vezes não observada por meio da baciloscopia tradicional e ocorre resposta imune patógeno-específica. As incapacidades físicas nos pacientes decorrem da neuropatia e osteopatia e podem ser irreversíveis. Essas deformidades podem avançar mesmo após a diminuição da carga bacilar com o final do tratamento poliquimioterápico. A presente tese teve por objetivo estudar as implicações da proteína PHEX nas alterações fisiopatológicas da hanseníase, em especial as alterações ósseas. A proteína PHEX (Phosphate-regulating gene with Homologies to Endopeptidase on the X chromosome) é expressa em várias células humanas e, no primeiro artigo que compõe essa tese, demonstramos que o M.leprae leva à diminuição da expressão de PHEX em linhagens de células de Schwann e osteoblastos humanos. Este efeito foi igualmente causado por outras espécies de micobactérias. No segundo manuscrito ora submetido, observamos que em leucócitos sanguíneos de pacientes hansenianos também ocorreu modulação negativa de PHEX. Este efeito não se relacionou com a capacidade de produção de citocinas inflamatórias frente ao M. leprae in vitro ou com alterações bioquímicas. O efeito inibidor da mineralização ocasionado pela modulação negativa de PHEX talvez contribua para a doença óssea da hanseníase, auxiliando a explicar a capacidade do M. leprae de penetrar e sobreviver no osso.

Knowledge of the patients regarding leprosy and adherence to treatment

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is known for its great disfiguring capacity and is considered an extremely serious disease to public health worldwide. The state of Ceará ranks 13th in number of cases of leprosy in Brazil, and fourth in Northeastern region, with an average of 2,149 new cases diagnosed every year. This study aimed to evaluate the knowledge of leprosy patients regarding treatment, and to assess the level of treatment adherence and its possible barriers. The study was conducted in the reference center for dermatology, from September 2010 to October 2010, in Fortaleza, Ceará. The study data were collected by means of a structured interview, along with the Morisky-Green test, in order to assess treatment adherence and barriers to adherence. A total of 70 patients were interviewed, out of whom 66 were new cases. The majority of patients were between 42 and 50 years old, and 37 (52.9%) were male. Most patients were clinically classified as presentingmultibacillary leprosy (80%), and 78.6% of them were from Fortaleza, Brazil. The Morisky-Green test indicated that 62.9% of patients presented a low level of adherence (p < 0.005), despite claiming to aware of the disease risks. However, it was observed that 57.1% of the patients had no difficulty adhering to treatment, while 38.6% reported little difficulty. This study shows that despite the patients claiming to be familiar with leprosy and its treatment, the Morisky-Green test clearly demonstrated that they actually were not aware of the principles of therapy, which is evidenced by the low degree of treatment adherence

Da negatividade a positividade: possível trânsito de saberes, práticas e representações sociais sobre o estigma da hanseníase

Leprosy is a chronic infectious-contagious disease, caused by Mycobacterium leprae, manifested by dermatological and neurological signs and symptoms and has great disabling power. It was marked by a strong stigma throughout its history, since its bearers represented a threat, target of fear and social contempt. Currently, leprosy has treatment and cure, and the need to separate the diseased from family and social environment is no more necessary. However, patients still suffer prejudice and discrimination. This study aimed to understand the social representations of leprosy that interfere modifying mental health of the patient with leprosy in relation to stigma and prejudice. This is a descriptive and exploratory study, with qualitative approach, which involved 22 users of the Special Care Clinic in Infectious Diseases at the Hospital Giselda Trigueiro, located in Natal / RN. They were in use of multidrug therapy in the period of data collection, were of both sexes, aged between 16 and 80 years of age and classified as paucibacillary or multibacillary. The study was approved by the UFRN Ethics in Research Committee. Data collection was performed by filling the questionnaire identification and then for conducting the semi-structured interview, which was recorded. After the end of data collection, there was the construction of tables and graphs, using the Microsoft Excel Start 2010 for proper characterization of the research subjects; and for the treatment of the data obtained from the interviews, was used the Content Analysis and based on the Theory of Social Representations. The subjects studied were mostly male (64%), married or in a stable relationship (68%), concentrated in the age group 50-60 years (36%) and 28-38 years (23%), had at most elementary education (65%) and were low-income (59%). Of the total respondents, 64% were classified as multibacillary, with predominantly dimorfous form, and 50% had disability grade I or II, with different periods of diagnosis. The reports originate two categories: 1. The negative meanings of illness and leprosy; and 2. The positive meanings of illness in leprosy, which were subsequently subdivided into subcategories. Thus, it was found that in the group studied, the social representation of leprosy experiences a moment of transition, as regards the understanding of the disease and its way of experiencing the disease process. Such representation is anchored in the quality of information on the disease of its bearers and aimed at an attempt to face the illness of leprosy as a "normal process". It was found in this study that the transition is due to the work of combating stigma and consequences of leprosy, which is able to gradually transform reality, both regarding the team work of reference, and in relation to a broader character, of actions of health education, which favors overcoming of psychosocial disabilities

WHO disability grade does not influence physical activity in Brazilian leprosy patients

Disability caused by leprosy may be associated with stigma. The aim of this work is to describe the degree of disability, quality of life and level of physical activity of individuals with leprosy and to identify possible correlations between these factors. Ninety-seven patients from two referral centres were studied. A complete medical history was taken and the World Health Organization degree of physical disability classification (WHO-DG), the International Physical Activity Questionnaire (IPAQ) and the Medical Outcome Study 36-item Short-form health Survey (SF36) were applied. The mean age of patients was 51 +/- 14.9 years old; participants were predominantly men, married, unemployed, had concluded treatment and had had lepromatous leprosy. The WHO-DG and the level of physical activity (P-value = 0.36) were not correlated. The WHO-DG showed that 72.2% of patients had disabilities, 37-1% of whom performed vigorous physical activities. No significant association was observed between the WHO-DG and the domains of the QoL SF-36 except for functional capacity (P-value = 0.02); the physical capacity is generally 'very good' when individuals have no disabilities and 'bad' with severe disabilities. In conclusion, the WHO-DG of leprosy patients does not affect the level of physical activities or quality of life except functional capacity. There is no significant association between physical activities and quality of life in these individuals.

Neurophysiological patterns of ulnar nerve neuropathy in leprosy reactions

Background: Leprosy neuropathy, despite being primarily demyelinating, frequently leads to axonal loss. Neurophysiological examination of the nerves during Type 1 (T1R) and Type 2 reactions (T2R) may give some insight into the pathophysiological mechanisms.Methods: Neurophysiological examinations were performed in 28 ulnar nerves during a clinical trial of steroid treatment effectiveness, 19 patients with T1R and nine with T2R. The nerves were monitored during a period of 6 months; there were eight assessments per nerve, for a total of 224 assessments. Nine neurophysiological parameters were assessed at three sites of the ulnar nerve. The compound motor action potential amplitudes elicited at wrist, elbow and above, as well as the conduction velocity and temporal dispersion across the elbow, were chosen to focus on the changes occurring in the parameters at the elbow tunnel.Results and Conclusion: Neurophysiological changes indicating axonal and demyelinating processes during both T1R and T2R were detected across the elbow. Changes in demyelination, i.e. a Conduction Block, as a primary event present during T2R, occurring as an acute phenomenon, were observed regularly; in T1R Temporal Dispersion, a subacute phenomenon, was seen. During treatment remyelination occurred after both types of reactions.

Laryngeal lesion in leprosy and the risk of aspiration

Leprosy affects the larynx, damaging its mucosa and sensory nerves and loss of sensation may result in aspiration of food and secretions. The laryngeal lesion may be insidious. Post-mortem studies showed bronchopneumonia that could have originated from aspiration. In patients with laryngeal symptoms, dysphagia or aspiration pneumonia loss of laryngeal sensation should be looked for.

A university extension course in leprosy: telemedicine in the Amazon for primary healthcare

There is a high prevalence of leprosy in the Amazon region of Brazil. We have developed a distance education course in leprosy for training staff of the Family Health Teams (FHTs). The course was made available through a web portal. Tele-educational resources were mediated by professors and coordinators, and included the use of theoretical content available through the web, discussion lists, Internet chat, activity diaries, 3-D video animations (Virtual Human on Leprosy), classes in video streaming and case simulation. Sixty-five FHT staff members were enrolled. All of them completed the course and 47 participants received a certificate at the end of the course. At the end of the course, 48 course-evaluation questionnaires were answered. A total of 47 participants (98%) considered the course as excellent. The results demonstrate the feasibility of an interactive, tele-education model as an educational resource for staff in isolated regions. Improvements in diagnostic skills should increase diagnostic suspicion of leprosy and may contribute to early detection.

Tele-education on Leprosy: Evaluation of an Educational Strategy

The purpose of this research was to evaluate educational strategies applied to a tele-education leprosy course. The curriculum was for members of the Brazilian Family Health Team and was made available through the São Paulo Telehealth Portal. The course educational strategy was based on a constructivist learning model where interactivity was emphasized. Authors assessed motivational aspects of the course using the WebMAC Professional tool. Forty-eight healthcare professionals answered the evaluation questionnaire. Adequate internal consistency was achieved (Cronbach's alpha = 0.79). More than 95% of queried items received good evaluations. Multidimensional analysis according to motivational groups of questions (STIMULATING, MEANINGFUL, ORGANIZED, EASY-TO-USE) showed high agreement. According to WebMAC's criteria, it was considered an awesome course. The tele-educational strategies implemented for leprosy disclosed high motivational scores.

Armadillo meat intake was not associated with leprosy in a case control study, Curitiba (Brazil)

Leprosy's progression and its maintained endemic status, despite the availability of effective treatments, are not fully understood and recent studies have highlighted the possibility of involved Mycobacterium leprae ambient reservoirs. Wild armadillos can carry leprosy and, because their meat is eaten by humans, development of the disease among armadillo meat consumers has been investigated. This study evaluated the frequency of armadillo meat intake among leprosy patients as well as age and gender matched controls with other skin diseases from a dermatological unit. Armadillo meat consumption among both groups was adjusted by demographic and socioeconomic covariates based on a conditional multiple logistic regression model. One hundred twenty-one cases and 242 controls were evaluated; they differed in socioeconomic variables such as family income, hometown population and access to treated water. The multivariate analysis did not show an association between the intake of armadillo meat and leprosy (odds ratio = 1.07; CI 95% 0.56-2.04), even when only cases with no known contacts were analyzed. We conclude that leprosy is not associated with the intake of armadillo meat in these patients.

Paracoccidioidomycosis: infiltrated, sarcoid-like cutaneous lesions misinterpreted as tuberculoid leprosy

Os Autores relatam um caso de paracoccidioidomicose diagnosticado como se fora hanseníase tuberculóide, tanto do ponto de vista clínico como histopatológico. Lesão cutânea de padrão sarcoídico é raramente observada como lesão inicial da paracoccidioidomicose em jovens e pode simular outras dermatoses infecciosas ou inflamatórias. O achado histológico de granuloma tuberculóide apresenta dificuldade diagnóstica similar. O tratamento realizado com dapsone, um derivado sulfamídico, pode ter retardado a evolução clínica esperada para o padrão clássico da paracoccidioidomicose tipo juvenil, o qual apenas se materializou 24 meses após a paciente ter iniciado tratamento como hanseníase.

Borderline leprosy: in situ and cytokine profile in supernatant of mononuclear of cell culture

In order to contribute to a better understanding of cytokine participation in borderline leprosy, in the present study we determined - by in vitro and in situ examinations - the production of these cytokine mediation in non-treated borderline tuberculoid (BT) patients and borderline lepromatous (BL) patients. Seven non-treated BT patients, 12 non-treated BL patients, besides 19 healthy individuals (control group), were evaluated. Peripheral blood mononuclear cells (PBMC) were stimulated or not with specific-M. leprae stimulus (whole and sonicated M. leprae antigens) and a non-specific stimulus. After 48 hours, supernatant was collected for TNF-alpha, IFN-gamma, IL-10 and TGF-beta1 cytokine determination by ELISA. Biopsies from cutaneous lesions were submitted to histological analysis and hematoxylin-eosin and Fite-Faraco stainings; the sections then underwent iNOS, IL-10 and TGF-beta1 in situ detection by immunohistochemistry. Cytokine quantification in PBMC supernatants from patients showed that BT patients produced higher levels of IFN-gamma. Compared to healthy individuals, both borderline patient groups produced lower levels of TGF-beta1 while BL patients generated lower IL-10 levels. The in situ iNOS expression was higher in BT patients compared to BL individuals. on the order hand, TGF-beta1 cytokine revealed a higher proportion of immunostained cells in BL patients. There was no significant difference in IL-10 level between BT and BL patients. Regarding cutaneous lesions, in BL patients there was a negative correlation between TGF-beta1 tissue expression and IL-10. Independently of the clinical form, we observed a positive correlation between TGF-beta1 and bacterial index as well as a negative correlation between the TGF-beta1 tissue expression and iNOS. The results even showed a positive correlation between iNOS tissue expression and production of IFN-gamma by PBMC stimulated with M. leprae antigens. Taken together, the histopathological and immunological observations reinforce the notion of immunological instability in borderline leprosy patients and indicating the participation of mixed cytokines profiles in these individuals, specifically a Th1 profile in BT patients and Th2 profile in BL patients, with a possible participation of T-regulatory lymphocytes.

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

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for-819C/T in leprosy susceptibility

Leprosy is a complex infectious disease influenced by genetic and environmental factors. The genetic contributing factors are considered heterogeneous and several genes have been consistently associated with susceptibility like PARK2, tumor necrosis factor (TNF), lymphotoxin-alpha (LTA) and vitamin-D receptor (VDR). Here, we combined a case-control study (374 patients and 380 controls), with meta-analysis (5 studies; 2702 individuals) and biological study to test the epidemiological and physiological relevance of the interleukin-10 (IL-10) genetic markers in leprosy. We observed that the -819T allele is associated with leprosy susceptibility either in the case-control or in the meta-analysis studies. Haplotypes combining promoter single-nucleotide polymorphisms also implicated a haplotype carrying the -819T allele in leprosy susceptibility (odds ratio (OR) = 1.40; P = 0.01). Finally, we tested IL-10 production in peripheral blood mononuclear cells stimulated with Mycobacterium leprae antigens and found that -819T carriers produced lower levels of IL-10 when compared with noncarriers. Taken together, these data suggest that low levels of IL-10 during the disease outcome can drive patients to a chronic and unprotective response that culminates with leprosy.