Tuberculose esofágica primária: relato de caso

Esophageal tuberculosis is an extremely rare event, accounting for 0.2 percent of these cases affecting the esophagus. Most of them are secondary to pulmonary disease. The authors present a case of primary esophageal tuberculosis in a 40 years old HIV-positive female.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

Influence de l'initiation de la traduction sur le changement programmé du cadre de lecture en -1 responsable de la synthèse des enzymes du virus de l’immunodéficience humaine de type 1

Le virus de l’immunodéficience humaine de type 1 (VIH-1) est responsable du syndrome de l’immunodéficience acquise (SIDA). Il faut identifier de nouvelles cibles pour le développement d’agents anti-VIH-1, car ce virus développe une résistance aux agents présentement utilisés. Notre but est d’approfondir la caractérisation de l’étape du changement de cadre de lecture ribosomique en -1 (déphasage -1) nécessaire à la production du précurseur des enzymes du VIH-1. Ce déphasage est programmé et effectué par une minorité de ribosomes lorsqu’ils traduisent la séquence dite glissante à un endroit spécifique de l’ARN messager (ARNm) pleine-longueur du VIH-1. L’efficacité de déphasage est contrôlée par le signal stimulateur de déphasage (SSF), une tige-boucle irrégulière située en aval de la séquence glissante. La structure du SSF est déroulée lors du passage d’un ribosome, mais elle peut se reformer ensuite. Nous avons montré que des variations de l’initiation de la traduction affectent l’efficacité de déphasage. Nous avons utilisé, dans des cellules Jurkat-T et HEK 293T, un rapporteur bicistronique où les gènes codant pour les luciférases de la Renilla (Rluc) et de la luciole (Fluc) sont séparés par la région de déphasage du VIH-1. La Rluc est produite par tous les ribosomes traduisant l’ARNm rapporteur alors que la Fluc est produite uniquement par les ribosomes effectuant un déphasage. L’initiation de ce rapporteur est coiffe-dépendante, comme pour la majorité des ARNm cellulaires. Nous avons examiné l’effet de trois inhibiteurs de l’initiation et montré que leur présence augmente l’efficacité de déphasage. Nous avons ensuite étudié l’effet de la tige-boucle TAR, qui est présente à l’extrémité 5’ de tous les ARNm du VIH-1. TAR empêche la liaison de la petite sous-unité du ribosome (40S) à l’ARNm et module aussi l’activité de la protéine kinase dépendante de l’ARN double-brin (PKR). L’activation de PKR inhibe l’initiation en phosphorylant le facteur d’initiation eucaryote 2 (eIF2) alors que l’inhibition de PKR a l’effet inverse. Nous avons étudié l’effet de TAR sur la traduction et le déphasage via son effet sur PKR en utilisant TAR en trans ou en cis, mais à une certaine distance de l’extrémité 5’ afin d’éviter l’interférence avec la liaison de la 40S. Nous avons observé qu’une faible concentration de TAR, qui active PKR, augmente l’efficacité de déphasage alors qu’une concentration élevée de TAR, qui inhibe PKR, diminue cette efficacité. Nous avons proposé un modèle où des variations de l’initiation affectent l’efficacité de déphasage en modifiant la distance entre les ribosomes parcourant l’ARNm et, donc, la probabilité qu’ils rencontrent un SSF structuré. Par la suite, nous avons déterminé l’effet de la région 5’ non traduite (UTR) de l’ARNm pleine-longueur du VIH-1 sur l’efficacité de déphasage. Cette 5’UTR contient plusieurs régions structurées, dont TAR à l’extrémité 5’, qui peut interférer avec l’initiation. Cet ARNm a une coiffe permettant une initiation coiffe-dépendante ainsi qu’un site d’entrée interne des ribosomes (IRES), permettant une initiation IRES-dépendante. Nous avons introduit cette 5’UTR, complète ou en partie, comme 5’UTR de notre ARNm rapporteur bicistronique. Nos résultats démontrent que cette 5’UTR complète inhibe l’initiation coiffe dépendante et augmente l’efficacité de déphasage et que ces effets sont dus à la présence de TAR suivie de la tige-boucle Poly(A). Nous avons aussi construit un rapporteur tricistronique où les ribosomes exprimant les luciférases utilisent obligatoirement l’IRES. Nous avons observé que cette initiation par l’IRES est faible et que l’efficacité de déphasage correspondante est également faible. Nous avons formulé une hypothèse pour expliquer cette situation. Nous avons également observé que lorsque les deux modes d’initiation sont disponibles, l’initiation coiffe dépendante est prédominante. Finalement, nous avons étudié l’effet de la protéine virale Tat sur l’initiation de la traduction et sur l’efficacité de déphasage. Nous avons montré qu’elle augmente l’initiation de la traduction et que son effet est plus prononcé lorsque TAR est située à l’extrémité 5’ des ARNm. Nous proposons un modèle expliquant les effets de Tat sur l’initiation de la traduction par l’inhibition de PKR ainsi que par des changements de l’expression de protéines cellulaires déroulant TAR. Ces résultats permettent de mieux comprendre les mécanismes régissant le déphasage du VIH-1, ce qui est essentiel pour le développement d’agents anti-déphasage.

The Nutritional Status of Children and Adolescents with HIV/AIDS on Antiretroviral Therapy

The objective of this cross-sectional study was to assess the nutritional status of children and adolescents with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) receiving highly active antiretroviral therapy (HAART). One hundred and eighteen subjects aged 6-19 years attending an outpatient clinic in Sao Paulo city were involved in the study. The following anthropometric measurements were assessed: weight, height, waist circumference and triceps and subscapular skinfold thickness. One (0.9%) adolescent was diagnosed with abdominal obesity based on waist circumference measurement; three (2.5%) adolescents were obese based on subscapular skinfold thickness. According to the body mass index, the population studied was mainly eutrophic. The prevalence of fat redistribution, a characteristic of patients with HIV/AIDS under HAART, was low. We advise the development of further studies to assess the nutritional status of children and adolescents with HIV/AIDS using anthropometric measurements as well as computed tomography to detect fat redistribution.

Autoimmunity in common variable immunodeficiency

immunodeficiency (CVID), the most common symptomatic primary immunodeficiency in adulthood. Different authors report high prevalences of autoimmune diseases in CVID, and several mechanisms have been proposed to explain this apparent paradox. Genetic predisposition, under current surveillance, innate and adaptive immunity deficiencies leading to persistent/recurrent infections, variable degrees of immune dysregulation, and possible failure in central and peripheral mechanisms of tolerance induction or maintenance may all contribute to increased autoimmunity. Conclusions Data on the clinical/immunological profile of affected patients and treatment are available mostly concerning autoimmune cytopenias, the most common autoimmune diseases in CVID. Treatment is based on conventional alternatives, in association with short experience with new agents, including rituximab and infliximab. Benefits of early immunoglobulin substitutive treatment and hypothetical premature predictors of autoimmunity are discussed as potential improvements to CVID patients` follow-up.

Adenosine deaminase activity as a biochemical marker of inflammatory response in goats infected by caprine arthritis-encephalitis virus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Darunavir: A Critical Review of Its Properties, Use and Drug Interactions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Consenso de imunização para crianças e adolescentes com doenças reumatológicas

Crianças e adolescentes com doenças reumatológicas apresentam maior prevalência de doenças infecciosas quando comparados com a população em geral, em decorrência de atividade da doença, possível deficiência imunológica secundária à própria doença, ou uso de terapia imunossupressora. A vacinação é uma medida eficaz para a redução da morbidade e mortalidade nesses pacientes. O objetivo deste artigo foi realizar um consenso de eficácia e segurança das vacinas em crianças e adolescentes com doenças reumatológicas infantis baseadas em níveis de evidência científica. Imunização passiva para os pacientes e orientações para as pessoas que convivem com doentes imunodeprimidos também foram incluídas. Os 32 pediatras reumatologistas membros do Departamento de Reumatologia da Sociedade de Pediatria de São Paulo (SPSP) e/ou da Comissão de Reumatologia Pediátrica da Sociedade Brasileira de Reumatologia elaboraram o consenso, sendo que alguns desses profissionais estão envolvidos em pesquisas e publicações científicas nesta área. A pesquisa dos termos eficácia e/ou segurança das diferentes vacinas em crianças e adolescentes com doenças reumatológicas foi realizada nas bases de Medline e Scielo, de 1966 até março de 2009, incluindo revisões, estudos controlados e relatos de casos. O grau de recomendação e o nível científico de evidências dos estudos foram classificados em quatro níveis para cada vacina. de um modo geral, as vacinas inativadas e de componentes são seguras nos pacientes com doenças reumatológicas, mesmo em uso de terapias imunossupressoras. Entretanto, vacinas com agentes vivos atenuados são, em geral, contraindicadas para os pacientes imunossuprimidos.

Cell-mediated and humoral immunity in West syndrome

The immunological status of five children with West syndrome consequent to previous cerebral lesions was investigated. Three children had West syndrome and two were in transition from West to Lennox-Gastaut syndrome. All of them showed cellular immunological deficiencies in the following tests: sensitization to DNCB, intracutaneous reaction to PHA, inhibition of leukocyte migration, blastic transformation of lymphocytes, T and B lymphocytes in peripheral blood and levels of serum immunoglobulins. These immunological deficiencies, of different degrees of severity, were associated with frequent infections in these children. A possible association between the immunological deficiencies and autoimmunity is discussed.

Lesões do trato gastrointestinal na síndrome da imunodeficiência adquirida: estudo de 45 necrópsias consecutivas.

This study was designed to evaluate retrospectively the frequency and etiology of the gastrointestinal (GI) lesions in 45 consecutive necropsies of adult patients with Acquired Immunodeficiency Syndrome (AIDS). Gross descriptions and histological sections of the GI tract, from mouth to anus, were reviewed. The slides were H&E stained, and when necessary special stains and immunohistochemical methods were also employed. There were lesions in GI tract in 37 (82.3%) patients; the mouth was the segment most frequently involved (73.3% of the cases), followed by the colon (55.5%). Multiple lesions occurred in 17 (37.7%) cases. Cytomegalovirus caused colonic lesions in 35.7% of the cases. Candidiasis was observed in 26.6% mainly in the mouth and herpes simplex (8.8%) was the important agent of esophageal lesions. Oral hairy leukoplasia associated with HPV was found in 16 (35.5%) cases. Neoplasia was diagnosed in 7 (15.5%) cases: four Kaposi's sarcoma, two anal intramucosal carcinomas and one gastric lymphoma. Our data confirm the high frequency and variety of GI tract alterations in AIDS.

Patologia do Coração na AIDS. Estudo de 73 Necropsias Consecutivas

Purpose - To study the incidence and the etiology of the cardiac lesions in AIDS patients. Methods - The autopsy protocols and the filled slides of the heart from 73 consecutive AIDS patients were reviewed. There were, at least, 2 slides of each heart stained by haematoxylin-eosin; when indicated, Ziehl-Nielsen, Gram and Gomori Grocott stains were used. Results - No cause of death was assigned to the heart. There was involvement of the heart in 66 (90%) cases. Marked atrophy of cardiac fibers with or without lipomatosis was observed in 38 patients. Interstitial infiltrates of myocardium were present in 38 necropsies and in 13 of these cases a probable pathogen was demonstrated: cryptococcus neoforms in three cases and mycobacteria tuberculosis, atypical mycobacteria, toxoplasma gondii, trypanosoma cruzi and cytomegalovirus in two cases each. Bacterial endocarditis was found in 4 autopsies and Kaposi sarcome in one. The pericardium was involved in 22 cases; in 12 there was only non specific mononuclear infiltration. Conclusion - Autopsy examination of the heart from AIDS patients revealed frequent pathologic involvement.

The deep mycoses in HIV infection

The deep mycoses are uncommon infections, usually acquired from the inhalation or ingestion of fungal spores, sometimes from the soil in areas of endemicity, such as in the Americas and south-east Asia, or from decaying vegetable matter. They are also seen in immunocompromised persons and, increasingly, in HIV-infected persons. Respiratory involvement is frequent, with granuloma formation, and mucocutaneous involvement may be seen. Oral lesions of the deep mycoses are typically chronic but non-specific, though nodular or ulcerative appearances are common. Person-to-person transmission is rare. In HIV disease, the most common orofacial involvement of deep mycoses has been in histoplasmosis, cryptococcosis, aspergillosis and zygomycosis. Diagnosis is usually confirmed by lesional biopsy although culture may also be valuable. Treatment is with amphotericin or an azole.

A comparative evaluation of open loop and closed loop drug administration strategies in the treatment of AIDS.

In recent years, many researchers in the field of biomedical sciences have made successful use of mathematical models to study, in a quantitative way, a multitude of phenomena such as those found in disease dynamics, control of physiological systems, optimization of drug therapy, economics of the preventive medicine and many other applications. The availability of good dynamic models have been providing means for simulation and design of novel control strategies in the context of biological events. This work concerns a particular model related to HIV infection dynamics which is used to allow a comparative evaluation of schemes for treatment of AIDS patients. The mathematical model adopted in this work was proposed by Nowak & Bangham, 1996 and describes the dynamics of viral concentration in terms of interaction with CD4 cells and the cytotoxic T lymphocytes, which are responsible for the defense of the organism. Two conceptually distinct techniques for drug therapy are analyzed: Open Loop Treatment, where a priori fixed dosage is prescribed and Closed Loop Treatment, where the doses are adjusted according to results obtained by laboratory analysis. Simulation results show that the Closed Loop Scheme can achieve improved quality of the treatment in terms of reduction in the viral load and quantity of administered drugs, but with the inconvenience related to the necessity of frequent and periodic laboratory analysis.

Manifestações otorrinolaringológicas em crianças com AIDS

Introduction: The study of otolaryngologic manifestations in children HIV + can lead to early diagnosis of AIDS, allowing specific treatment, responsible by reduced morbidity and mortality. Objectives: Detect the otolaryngologic manifestations in children with AIDS and alert to the importance of the early diagnosis. Study design: Clinical prospective. Material and method: We evaluated 22 children with AIDS assisted at Faculdade de Medicina de Botucatu (São Paulo, Brasil). The medical records were reviewed and the children were submitted to otolaryngologic and hearing acuity exams. Results: We evaluated 12 boys and 10 girls, whose ages ranged from 8 months to 12 years. In B and C clinical classification were included 18 children who were using anti-retroviral medicaments. Physical examination mainly indicated cervical lymphadenopathy (18 cases), paleness of the nasal mucous membrane with abundant mucous secretion over the nasal epithelium (15 cases) and retraction of tympanic membranes (seven cases). The main otolaryngologic diagnoses were: rhinosinusitis (16 cases), oral candidiasis (13 cases), inadequate eustachian tube function (seven cases) and recurrent tonsillar infections (six cases). Conductive hearing loss were detected in 4 children. No child presented sensorineural hearing loss. Conclusions: The main otolaryngologic manifestations presented by the children with HIV virus were rhinosinusitis, oral candidiasis, inadequate eustachian tube function and recurrent tonsillar infections. The allergic aspect of the nasal mucous membrane and the cervical lymphadenopathy were frequent signs and could alert the otolaryngologyst to AIDS during the exam.