70 research outputs found
Mucopolissacaridoses : caracterização das alterações cardiovasculares e avaliação da segurança do tratamento com losartana
As mucopolissacaridoses (MPS) são um grupo de doenças lisossômicas causadas pelo acúmulo de glicosaminoglicanos, associadas a um acometimento multissistêmico e com significativa sobreposição clínica entre seus tipos. Os problemas cardiovasculares estão entre as manifestações mais comumente observadas e também estão entre as principais causas de morbimortalidade nesses pacientes. Recentemente, a dilatação de raiz de aorta (DRA) tem sido apontada como uma alteração frequente em diferentes tipos de MPS. Para algumas das manifestações cardiovasculares, como a DRA e as doenças valvares, não há tratamento eficaz atualmente disponível. Nesse sentido, nós inicialmente revisamos os achados ecocardiográficos de 69 pacientes com diferentes tipos de MPS (25 com MPS I, 21 com MPS II, 16 com MPS IVA e 7 com MPS VI) e confirmamos que a DRA é um achado frequente nas MPS, sendo especialmente prevalente em pacientes com MPS IVA e MPS VI. Além disso, verificamos que a terapia de reposição enzimática (TRE) parece ter pouco impacto sobre seu surgimento e progressão. Na sequência, realizamos uma avaliação mais extensa em 76 pacientes com MPS, avaliando parâmetros relacionados à hipertrofia ventricular esquerda, hipertensão pulmonar, função sistólica e condução atrioventricular. Observamos que o uso de TRE esteve associado à redução de parâmetros relacionados à presença de hipertrofia ventricular esquerda, porém com efeito limitado sobre outros parâmetros. Considerando o potencial terapêutico da losartana sobre a doença cardíaca nas MPS, verificado em modelos animais, foi desenhado um ensaio clínico de fase II, randomizado, duplo cego, com o objetivo de avaliar a segurança e a eficácia da losartana para o tratamento de manifestações cardiovasculares em pacientes com MPS IVA e VI. Os resultados obtidos na etapa inicial do estudo demonstraram um perfil de segurança favorável em pacientes com MPS IVA e trouxeram dados i Os resultados obtidos na etapa inicial do estudo demonstraram um perfil de segurança favorável em pacientes com MPS IVA e trouxeram dados importantes para projetar a continuidade da avaliação da losartana como agente terapêutico nas MPS.The mucopolysaccharidoses (MPS) are a group of lysosomal diseases caused by the accumulation of glycosaminoglycans, associated with multisystemic involvement and with significant clinical overlap among their types. Cardiovascular problems are among the most commonly observed manifestations and are also among the main causes of mortality in these patients. Recently, aortic root dilation (ARD) has been identified as a frequent abnormality in different types of MPS. For some of the cardiovascular manifestations, such as ARD and valvular diseases, there is currently no effective treatment available. In this sense, we initially reviewed the echocardiographic findings of 69 patients with different types of MPS and confirmed that ARD is a frequent finding in mucopolysaccharidoses, being especially prevalent in patients with MPS IVA and MPS VI. In addition, we found that enzyme replacement therapy (ERT) appears to have little impact on its occurrence and progression. Thereafter, we carried out a more extensive evaluation in 76 patients with MPS, evaluating parameters related to ventricular hypertrophy, pulmonary hypertension, systolic function and cardiac conduction and we observed that the use of ERT was associated with a reduction in parameters related to the presence of left ventricular hypertrophy, but with limited effect on other parameters. Considering the therapeutic potential of losartan on heart disease in MPS verified in animal models, a randomized, double-blind, phase II clinical trial was eventually designed to assess the safety and efficacy of losartan for treatment of cardiovascular disease in patients with MPS IVA and VI. The initial results showed a favorable safety profile in patients with MPS IVA and bring important data for the continuity of the evaluation of losartan as a therapeutic agent in the MPS
SEPTIC SHOCK IN PATIENT WITH DISSEMINATED HISTOPLASMOSIS ASSOCIATED WITH AIDS: A CASE REPORT
SUMMARY Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum, which may present itself as a serious infection in immunocompromised individuals. We present a case of 31-year-old female with newly diagnosed HIV infection and history of fever, general and respiratory symptoms and diffuse hyperchromic papules through the body. She was admitted, with rapid progression to septic shock, and the presence of neutrophils filled with yeast-like organisms was detected on peripheral blood smear hematoscopia on the third day of hospitalization. The following is a brief review on the clinical picture and management of histoplasmosis.RESUMO A histoplasmose é micose sistêmica causada por Histoplasma capsulatum, a qual pode se apresentar de forma grave em indivíduos imunocomprometidos. Neste trabalho, apresenta-se o caso de paciente feminino, 31 anos, com diagnóstico recente de infecção por HIV e quadro de febre, sintomas gerais e respiratórios e pápulas hipercrômicas difusas pelo corpo. Foi internada, apresentando progressão rápida para choque séptico, sendo detectada a presença de leveduras inclusas em neutrófilos à hematoscopia no terceiro dia de internação. Apresenta-se uma revisão breve sobre a apresentação e o manejo clínico da histoplasmose
Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease : functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome
Objectives: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. Methods: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. Results: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients). Patients’ primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation. Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. Conclusion: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy
Long-term restoration of alpha-L-iduronidase activity in fibroblasts from patients with mucopolysaccharidosis type I after non-viral gene transfer
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to deficiency of alpha-L-iduronidase (IDUA). Limitations such as need of weekly injection, high morbidity and mortality and high cost of the current treatments show the need for new approaches to treat this disease. In this work we aimed to correct fibroblasts from a MPS I patient using non-viral gene therapy. Using a plasmid encoding the human IDUA cDNA, we achieved stable high IDUA levels in transfected fibroblasts up to 6 months of treatment. These results serve as proof-of concept that a non-viral approach can correct the enzyme deficiency in cells from lysosomal storage disorders patients, which can be used as a tool for research a series of disease aspects. Future studies will focus on verify if this approach can be useful in small animals and clinical trials
Progression of cardiovascular manifestations in adults and children with mucopolysaccharidoses with and without enzyme replacement therapy
Background: Cardiovascular involvement is among the main features of MPS disorders and it is also a significant cause of morbidity and mortality. The range of manifestations includes cardiac valve disease, conduction abnormalities, left ventricular hypertrophy, and coronary artery disease. Here, we assessed the cardiovascular manifestations in a cohort of children and adults with MPS I, II, IV, and VI, as well as the impact of enzyme replacement therapy (ERT) on those manifestations. Methods: We performed a chart review of 53 children and 23 adults with different types of MPS that had performed echocardiograms from January 2000 until October 2018. Standardized Z scores were obtained for heart chamber sizes according to the body surface area. When available, echocardiographic measurements that were performed before ERT and at least 18 months after that date were used for the assessment of pre- and post-treatment parameters. Results: Left side valvular disease was a frequent finding, with mitral and aortic thickening being reported in most patients in all four MPS types. Left atrium dilatation was present in 26% of the patients; 25% had increased relative wall thickness; 28% had pulmonary hypertension. The cardiovascular involvement was, in general, more prevalent and more severe in adults than in children, including conduction disorders (40 vs. 16%), mitral stenosis (26 vs. 6%), aortic stenosis (13 vs. 4%), and systolic dysfunction (observed in only one adult patient). ERT promoted a significant reduction of the left ventricular hypertrophy parameters, but failed to improve valve abnormalities, pulmonary hypertension, and left atrial dilatation. Conclusions: Adult patients with MPS may develop severe cardiovascular involvement, not commonly observed in children, and clinicians should be aware of the need for careful monitoring and timely management of those potentially life-threatening complications. Our results also confirm the impact of long-term ERT on left ventricular hypertrophy and its limitations in reversing other prevalent cardiovascular manifestations
Precision medicine for lysosomal disorders
Precision medicine (PM) is an emerging approach for disease treatment and preventionthat accounts for the individual variability in the genes, environment, and lifestyle of each person.Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primarylysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzymeactivators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and thephenotype of the affected individual depends on the type of substrate and where it accumulates,which may be impacted by the type of genetic change and residual enzymatic activity. LDs areindividually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapiesare already available for several LDs, and many more are in development. Early identification mayenable disease course prediction and a specific intervention, which is very important for clinicaloutcome. Driven by advances in omics technology, PM aims to provide the most appropriatemanagement for each patient based on the disease susceptibility or treatment response predictionsfor specific subgroups. In this review, we focused on the emerging diagnostic technologies that mayhelp to optimize the management of each LD patient and the therapeutic options available, as well asin clinical developments that enable customized approaches to be selected for each subject, accordingto the principles of PM
Investigação de lipodistrofia sindrômica conduz a diagnóstico de síndrome autoinflamatória relacionada ao proteassoma
LIGA ACADÊMICA:: INSTRUMENTO DE ENSINO, PESQUISA E EXTENSÃO UNIVERSITÁRIA
As Ligas Acadêmicas são grupos formados por estudantes que, sob orientação dedocentes, organizam atividades extracurriculares de ensino, pesquisa e extensãouniversitária numa determinada área da saúde. Este trabalho tem como propósitorelatar a experiência de uma liga acadêmica de cirurgia no norte de MinasGerais. Para esse fim, utilizou-se o relatório das atividades solicitado aosacadêmicos e exigido pela Coordenadoria de Extensão Comunitária da universidadeem que ela está vinculada, entre agosto de 2008 a junho de 2010. Foiobservado que as atividades realizadas na liga acadêmica permitiram aos seusintegrantes abordar temas relacionados à Cirurgia (ensino), participar deprojetos de iniciação científica (pesquisa) e promover ações frente à comunidade (extensão). Desse modo, foi proporcionado o aprofundamento doconhecimento relacionado à Cirurgia e permitiu-se o desenvolvimento dehabilidades na área
Gorlin-Goltz Syndrome: case report and review of literature
Description of a case report of Gorlin-Goltz Syndrome diagnosed in a male newborn who presented increased head circumference and bifid ribs. Mother and grandmother presented typical physical findings of the syndrome, including palmar pits, odontogenic cysts, and history of multiple skin cancer resections. The diagnosis was based on clinical findings of three relatives. A literature review is also presented
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