Potentiation of dapsone induced methemoglobinemia by N-acetylcysteinc in rats

Dapsone (DDS) (4,4` diaminodiphenylsulfone), the drug of choice for the treatment of leprosy, frequently induces hemolytic anemia and methemoglobinemia. N-hydroxylation, one of the major pathways of biotransformation, has been constantly related to the methemeglobinemia after the use of the drug. In order to prevent the dapsone-induced hemotoxicity, N-acetylcysteine, a drug precursor of glutathione, was administered in combination with DDS to male Wistar rats, weighting 220-240 g. The animals were then anaesthetized and blood was collected from the aorta for determination of plasma DDS concentration by HPLC, determination of methemoglobinemia and glutathione by spectrophotometry, and for biochemical and hematological parameters. Our results showed that N-acetylcysteine enhanced dapsone-induced methemoglobinemia due to increased dapasone plasmatic concentration and consequent increased N-hydroxylamine formation. We concluded that drug interactions with dapsone require individually studies in order to avoid undesirable effects of dapsone.

Charcot`s arthropathy secondary to herpetic encephalitis sequelae: an unusual presentation

Neuropathic arthropathy (Charcot`s arthropathy) is a progressive articular disease associated with a reduced sensorial and protector proprioceptive reflex. Its etiology includes many different conditions such as syringomyelia, traumatic lesion causing medullary deformity, spina bifida, diabetic neuropathy, leprosy neuropathy, neurofibromatosis, amyloid neuropathy, alcohol, and repetitive injection of hydrocortisone into joints, among others. However, the relationship between Charcot`s arthropathy and herpetic encephalitis has not yet been described. Herpes encephalitis causes acute and chronic diseases of the peripheral or central nervous system. It can manifest as subacute encephalitis, recurrent meningitis, or myelitis. It can also resemble psychiatric syndromes, diplopia, sensory changes in the face and limbs, personality changes, frontal dysexecutive syndrome, stiff neck, subclinical alterations of the vestibular function, intracranial hypertension, convulsion, hemiparesis, and generally includes motor components, among others. On the other hand, pure peripheral sensory disturbance has not been described. In this article, we report the clinical case of a patient with Charcot`s arthropathy secondary to pure peripheral sensory polyneuropathy as a consequence of progressive herpetic encephalitis sequelae. In this article, the authors report the first case of Charcot`s arthropathy secondary to herpetic encephalitis.

Decrease in Mycobacterium tuberculosis specific immune responses in patients with untreated psoriasis living in a tuberculosis endemic area

Tuberculosis has emerged as a major concern in patients with immuno-mediated diseases, including psoriasis, undergoing treatment with biologicals. However, it is not known whether the chronically activated immune system of psoriasis patients interferes with their Mycobacterium tuberculosis (Mtb)-specific immunity, especially in tuberculosis-endemic areas like Brazil. We evaluated T-cell responses to a Mtb lysate and to the recombinant Mtb proteins ESAT-6 and Ag85B of tuberculin skin test (TST) positive and TST negative patients with severe or mild/moderate, untreated psoriasis in three different assays: lymphocyte proliferation, enzyme immunoassay for interferon (IFN)-gamma and interleukin (IL)-10 production by peripheral blood mononuclear cells and overnight enzyme immunospot (ELISpot) for enumerating IFN-gamma-secreting cells. In our cohort, a low proportion (29%) of the severe psoriasis patients tested were TST-positive. IFN-gamma and IL-10 secretion and T-cell proliferation to Mtb antigens were reduced in TST-negative but not in TST-positive patients with severe psoriasis when compared to healthy controls with the same TST status. Similarly, severe psoriasis patients had decreased cytokine secretion and proliferative response to phytohemagglutinin. However, most psoriasis patients and healthy controls showed detectable numbers of IFN-gamma-secreting effector-memory T-cells in response to Mtb antigens by ELISpot. TST-negative, mild/moderate psoriasis patients had responses that were mostly intermediary between TST-negative controls and severe psoriasis patients. Thus, patients with severe psoriasis possess decreased anti-Mtb central memory T-cell responses, which may lead to false-negative results in the diagnosis of TB infection, but retain T-cell memory-effector activity against Mtb antigens. We hypothesize that the latter may confer some protection against tuberculosis reactivation.

Erythema elevatum diutinum presenting with a giant annular pattern

A 45-year-old woman presented with a 3-year history of cutaneous lesions. Clinical examination revealed red-yellow to brownish infiltrated papules coalescing into annular-shaped plaques of several sizes with a hyperpigmented center affecting the abdomen and lower limbs, as well as multiple firm nodules on the right palm, elbows, and knees (Fig. 1a-c). The patient also reported sporadic arthralgia and low fever. She had been treated for leprosy for 2 years with multidrug therapy (clofazimine, dapsone, and rifampicin), with complete remission of the lesions during treatment, but recurrence after discontinuation. Histologic examination of a biopsy specimen taken from the cutaneous lesions showed an interstitial inflammatory infiltrate with the presence of many neutrophils and occasional foamy histiocytes (Fig. 2a). A pattern of perivascular eosinophilic fibrosis was observed in a biopsy specimen from a nodule (Fig. 2b). Special stains for acid-fast bacilli and fungi were negative. Laboratory findings included elevated immunoglobulin A (IgA) serum levels (1016 mg/dL; normal range, 69-382 mg/dL), elevated beta-globulin, and strong tuberculin reactivity. Normal or negative tests included direct immunofluorescence, serum immunofixation, anti-streptolysin O, and chest radiography. Autoimmune disorders and inflammatory intestinal diseases were excluded. The patient was treated with dapsone, 100 mg/day, with great improvement of the clinical picture. Hyperpigmented residual macules and some fibrotic nodules remained after 3 months.

Accuracy of store-and-forward diagnosis in leproy

Telemedicine might increase the speed of diagnosis for leprosy and reduce the development of disabilities. We compared the accuracy of diagnosis made by telemedicine with that made by in-person examination. The cases were patients with suspected leprosy at eight public health clinics in outlying areas of the city of Sao Paulo. The case history and clinical examination data, and at least two clinical images for each patient, were stored in a web-based system developed for teledermatology. After the examination in the public clinic, patients then attended a teaching hospital for an in-person examination. The benchmark was the clinical examination of two dermatologists at the university hospital. From August 2005 to April 2006, 142 suspected cases of leprosy were forwarded to the website by the doctors at the clinics. Of these, 36 cases were excluded. There was overall agreement in the diagnosis of leprosy in 74% of the 106 remaining cases. The sensitivity was 78% and the specificity was 31%. Although the specificity was low, the study suggests that telemedicine may be a useful low-cost method for obtaining second opinions in programmes to control leprosy.

Infectious diseases in paediatric pathology: experience from a developing country

Infectious and parasitic diseases have always challenged man. Although many of them are typically seen in some areas of the world and can be adequately managed by just improving socioeconomic status and sanitary conditions, they are still quite prevalent and may sometimes be seen outside their original geographical areas. Human migration due to different reasons, tourism, blood transfusion and solid organ transplantation has created new concerns for health professionals all over the world. If not for diagnostic purposes, at least these tropical and infectious diseases should be largely known because their epidemiology, pathogenesis, host/parasite interaction, inflammatory and reparative responses are quite interesting and teach us about human biology. Curiosity is inherent to pathology practice and so we are compelled to look for things other than tumours or degenerative diseases. This review focuses on infectious and parasitic diseases found in a developing country and brings up-to-date information on diseases caused by viruses (dengue, yellow fever), bacteria (typhoid fever, leprosy), parasites (Chagas` disease, cutaneous and visceral leishmaniasis, amoebiasis, Capillaria hepatica, schistosomiasis, cysticercosis) and caused by fungi (paracoccidioidomycosis, cryptococcosis, histoplasmosis) that may be useful for pathologists when facing somewhat strange cases from developing countries.

Molecular biology in tropical dermatoses

Initially, basic concepts are presented concerning the cell, genetic code and protein synthesis, and some techniques of molecular biology, such as PCR, PCR-RFLP, DNA sequencing, RT-PCR and immunoblotting. Protocols of nucleotides and of proteins extraction are supplied, such as salting out in peripheral blood allied to phenol-chloroform and trizol methods in skin samples. To proceed, commented examples of application of those techniques of molecular biology for the etiologic diagnosis and for research in tropical dermatoses, with emphasis to American tegumentary leishmaniasis and leprosy are presented.

Involvement of NO in the inhibitory effect of Calotropis procera latex protein fractions on leukocyte rolling, adhesion and infiltration in rat peritonitis model

Aim of the study: The latex of Calotropis procera has been used in the traditional medicinal system for the treatment of leprosy, ulcers, tumors, piles and diseases of liver, spleen, abdomen and toothache. it comprises of a non-dialyzable protein fraction (LP) that exhibits anti-inflammatory properties and a dialyzable fraction (DF) exhibiting pro-inflammatory properties. The present study was carried out to evaluate the effect of LP sub-fractions on neutrophil functions and nociception in rodent models and to elucidate the mediatory role of nitric oxide (NO). Material and methods: The LP was subjected to ion exchange chromatography and the effect of its three sub-fractions (LP(PI), LP(PII), and LP(PIII)) thus obtained was evaluated on leukocyte functions in the rat peritonitis model and on nociception in the mouse model. Results: LP sub-fractions exhibit distinct protein profile and produce a significant decrease in the carrageenan and DF induced neutrophil influx and exhibit anti-nociceptive property. The LP and its sub-fractions produced a marked reduction in the number of rolling and adherent leukocytes in the mesenteric microvasculature as revealed by intravital microscopy. The anti-inflammatory effect of LP(PI), the most potent anti-inflammatory fraction of LP, was accompanied by an increase in the serum levels of NO. Further, our study shows that NO is also involved in the inhibitory effect of LP(PI) on neutrophil influx. Conclusions: Our study shows that LP fraction of Calotropis procera comprises of three distinct sets of proteins exhibiting anti-inflammatory and anti-nociceptive properties of which LP(PI) was most potent in inhibiting neutrophil functions and its effects are mediated through NO production. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Dorsal cutaneous branch of the ulnar nerve: a light and electron microscopy histometric study

This study describes the normal morphology and morphometry of the dorsal cutaneous branch of the ulnar nerve (DCBU) in humans. Fourteen nerves of eight donors were prepared by conventional techniques for paraffin and epoxy resin embedding. Semiautomatic morphometric analysis was performed by means of specific computer software. Histograms of the myelinated and unmyelinated fiber population and the G-ratio distribution of fibers were plotted. Myelinated fiber density per nerve varied from 5,910 to 10,166 fibers/mm(2), with an average of 8,170 +/- 393 fibers/mm(2). The distribution was bimodal with peaks at 4.0 and 9.5 mu m. Unmyelinated fiber density per nerve varied from 50,985 to 127,108, with an average of 78,474 +/- 6, 610 fibers/mm(2), with a unimodal distribution displaying a peak at 0.8 mu m. This study thus adds information about the fascicles and myelinated and unmyelinated fibers of DCBU nerves in normal people, which may be useful in further studies concerning ulnar nerve neuropathies, mainly leprosy neuropathy.

Detection of cytokines and nitric oxide synthase in skin lesions of Jorge Lobo`s disease patients

Studies investigating the immunopathological aspects of Jorge Lobo`s disease have shown that the inflammatory infiltrate consists mainly of histiocytes and multinucleated giant cells involving numerous yeast-like cells of Lacazia loboi, with the T lymphocytes more common than B lymphocytes and plasma cells. The quantification of cytokines in peripheral blood mononuclear cells culture supernatant has revealed alterations in the cytokines profile, characterized by predominance of a Th2 profile. In view of these findings and of the role of cytokines in cell interactions, the objective of the present study was to investigate the presence of the cytokines IL-10, TGF-ss 1 and TNF-alpha, as well as iNOS enzyme in granulomas induced by L. loboi. Histological sections obtained from skin lesions of 16 patients were analyzed by immunohistochemistry for the presence of these cytokines and iNOS. The results showed that TGF-ss 1 was the cytokine most frequently expressed by cells present in the inflammatory infiltrate, followed by IL-10. There was a minimum to discrete positivity of cells expressing TNF-alpha and iNOS. The results suggest that the presence of immunosuppressive cytokines in skin lesions of patients with the mycosis might be responsible for the lack of containment of the pathogen as demonstrated by the presence of numerous fungi in the granuloma.

O isolamento no Hospital Colônia Pedro Fontes, Itanhenga/ES e a caracterização da população do Educandário Alzira Bley no período de 1937 a 1979

Caracteriza e analisa a população do Educandário, com as informações provenientes de uma fonte de dados documental e histórica contida nos dois livros de registros do Educandário e seus arquivos fotográficos. As informações sobre as 3.432 pessoas compõem um banco de dados que foi construído durante a realização desta pesquisa e as fotografias foram digitalizadas. O Educandário Alzira Bley, localiza-se na BR 101 - km 9, bairro de Itanhenga - Cariacica/ES. No estudo foram realizadas entrevistas semiestruturadas com funcionários e ex-internos do Educandário, que deram vida e movimento às análises dos gráficos e tabelas elaborados a partir do banco de dados. Para o embasamento teórico do estudo da população são empregados conceitos pertinentes à transição demográfica e à transição epidemiológica, às migrações forçadas, às redes migratórias e às características da população (sexo, idade, cor, origem e suas variações) que forneceram os elementos para a análise do estado da população em diferentes momentos históricos. A Geografia Histórica completa os referenciais teóricos desta investigação, pois muitas características geográficas requerem estudos históricos para uma explicação satisfatória de como chegaram ao que são hoje. As fotografias, os depoimentos e livros de registros do Educandário propiciaram a caracterização da população que passou e/ou viveu no Educandário Alzira Bley ao longo do período das internações compulsórias no Hospital Colônia Pedro Fontes (1937-1979). Com a realização desta investigação chegamos às seguintes conclusões: a) cada geração é vítima do conhecimento científico do seu tempo; b) a transição demográfica encontrava-se em sua primeira fase nos meados do século XX, e os índices elevados de mortalidade e de fecundidade eram observados na população estudada; c) a transição epidemiológica, também em curso no Espírito Santo era caracterizada por elevada incidência das doenças infectocontagiosas, dentre as quais a hanseníase era ainda uma doença sem cura. d) o isolamento dos hansenianos em hospitais colônias, bem como seus filhos em preventórios foram movimentos de migração forçada; e) a internação compulsória dos hansenianos em hospitais colônias desencadeava uma migração em rede de familiares e demais parentes e amigos que pudessem estar com a doença.

O estigma do preconceito : um estudo sobre representações de pacientes portadores de hanseníase no Município de Pedras de Fogo – Paraíba, Brasil

O objetivo desta pesquisa foi elaborar uma análise das Representações Sociais sobre a hanseníase e das condições sociais geradoras desta doença em pacientes do município paraibano de Pedras de Fogo, visto que o caráter cultural da enfermidade afeta a inserção do paciente com hanseníase na sociedade. Optou-se pela abordagem de natureza qualitativa. A população do estudo constituiu-se dos 11 pacientes diagnosticados no ano de 2005 no município. Os instrumentos utilizados para coleta de dados foram: os prontuários dos pacientes, um roteiro para entrevista semiestruturada, que foi gravada, após autorização dos sujeitos, com questões norteadoras para verificar as representações da doença, e também um questionário baseado em parâmetros do IBGE, do qual constavam a identificação e algumas características sociais, econômicas, educacionais e domiciliares do entrevistado. Como resultados observou-se que a maioria dos pacientes era do sexo feminino (72,72%); apresentavam baixo grau de alfabetização (45,45% eram analfabetos) e apenas um (9,09%) era universitário. Constatou-se a falta de emprego entre os entrevistados (somente 18,18% possuíam trabalho fixo); a renda mensal variou de ½ a 3 salários mínimos e só uma família (9,09%) apresentou rendimentos de 5 salários. Quanto às condições de moradia, a maioria das casas era de alvenaria e próprias, com banheiros e sanitários, tinham coleta de lixo e abastecimento de água de rede geral, porém todas com esgoto a céu aberto. Todos possuíam TV e, grande parte, também rádio. Quanto às Representações, os sujeitos do estudo tinham as lesões de pele e deformidades como maiores inquietações, alguns tentavam ocultar, enquanto outros arriscavam com ‘falsa naturalidade’ assumir a condição de hansenianos, o que fazia mudar suas identidades (virtual e real), num jogo de aceitação social, em que a mancha era o estigma para a exclusão. Assim, conclui-se que os pacientes incorporam os conhecimentos sobre a doença, atribuindo-lhes significados de acordo com suas crenças e valores. Por conseguinte, a maioria sofreu estigma ou se autoestigmatizou, sendo esta situação encontrada mesmo entre os que tiveram apoio da família e de amigos.

The experimental granuloma: a hypothesis to explain the persistence of the lesion

Granulomatous inflammation is the morphological substrate of a variety of important infectious diseases such as tuberculosis, leprosy, schistosomiasis and others. Nevertheless, although many aspects of this special type of inflammation are known, fundamental questions concerning granuloma formation, persistence, fate and significance for host-parasite relationships still remain to be elucidated. In this brief review, the basic and more relevant literature related to experimental investigations on granuloma physiopathology is presented. Based on recent investigations performed in our laboratory showing that MDF (Macrophage Deactivating Fator) secreted by epithelioid cells and characterized as the calcium-binding protein protein MRP-14 deactivates activated macrophages, a hypothesis to explain the persistence of granulomatous inflammation is put forward

The hamster cheek pouch: an immunologically privileged site suitable to the study of granulomatous infections

The hamster check pouch is an invagination of oral mucosa, characterized histologically as skin-like. In this paper we describe anatomical, histological and embriological features of the pouch and coment on the pouch as an immunologically privileged site since it lacks lymphatic drainage and has few Langerhans cells. We present the review from literature and our observations after inoculation in the pouch of mycobacteriae (BCG, Mycobacterium tuberculosis and Mycobacterium leprae) and a fungus (Paracoccidioides brasiliensis). Lesions in the pouch were granulomatous but smaller and long lasting; even granulomatous, the reaction was inefficient to control the proliferation of agents compared with inoculation in other sites, except for BCG. Appearance of immunity was also delayed or absent and, when it was detected, a sharp decrease in number of agents in pouch lesions was observed. These observations make the pouch an interesting site for the study of the role of immune system in infeccious diseases and in granuloma formation.

Immunological status of ENL (Erythema Nodosum Leprosum) patients: its relationship to bacterial load and levels of circulanting IL-2R

Recent data suggest that the clinical course of reactional states in leprosy is closely related to the cytokine profile released locally or systemically by the patients. In the present study, patients with erythema nodosum leprosum (ENL) were grouped according to the intensity of their clinical symptoms. Clinical and immunological aspects of ENL and the impact of these parameters on bacterial load were assessed in conjunction with patients' in vitro immune response to mycobacterial antigens. In 10 out of the 17 patients tested, BI (bacterial index) was reduced by at least 1 log from leprosy diagnosis to the onset of their first reactional episode (ENL), as compared to an expected 0.3 log reduction in the unreactional group for the same MDT (multidrug therapy) period. However, no difference in the rate of BI reduction was noted at the end of MDT among ENL and unreactional lepromatous patients. Accordingly, although TNF-alpha (tumor necrosis factor) levels were enhanced in the sera of 70.6% of the ENL patients tested, no relationship was noted between circulating TNF-alpha levels and the decrease in BI detected at the onset of the reactional episode. Evaluation of bacterial viability of M. leprae isolated from the reactional lesions showed no growth in the mouse footpads. Only 20% of the patients demonstrated specific immune response to M. leprae during ENL. Moreover, high levels of soluble IL-2R (interleukin-2 receptor) were present in 78% of the patients. Circulating anti-neural (anti-ceramide and anti-galactocerebroside antibodies) and anti-mycobacterial antibodies were detected in ENL patients' sera as well, which were not related to the clinical course of disease. Our data suggest that bacterial killing is enhanced during reactions. Emergence of specific immune response to M. leprae and the effective role of TNF-alpha in mediating fragmentation of bacteria still need to be clarified.