20 research outputs found
Respiratory manifestations in late-onset Pompe disease: a case series conducted in Brazil
Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment
Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions
Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial
Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402
Atenção aos defeitos congênitos no Brasil: panorama atual Birth defects and health strategies in Brazil: an overview
O impacto dos defeitos congênitos no Brasil vem aumentando progressivamente, tendo passado da quinta para a segunda causa dos óbitos em menores de um ano entre 1980 e 2000, apontando para a necessidade de estratégias específicas na política de saúde. Foram localizadas, no Brasil, direcionadas aos defeitos congênitos, ações governamentais e não-governamentais. Estas envolvem serviços de informação sobre agentes teratogênicos na gravidez e sobre doenças metabólicas geneticamente determinadas, monitorização de defeitos congênitos, programa de triagem neonatal e tratamento de algumas doenças genéticas, imunização contra rubéola, além da fortificação de farinhas com ácido fólico como ação preventiva de certos defeitos congênitos. Apesar da importância de tais iniciativas, é pouco provável que seja possível atender à questão dos defeitos congênitos de forma integrada. Para a efetivação de um sistema de atenção voltado aos defeitos congênitos, deverá ser formulada política específica, de âmbito nacional, com a participação ativa do Ministério da Saúde, utilizando, como espinha dorsal, os serviços de genética existentes. Só assim, será possível a estruturação de uma rede regionalizada, hierarquizada e funcional voltada à atenção aos defeitos congênitos no Brasil.<br>Birth defects have increased progressively in Brazil, shifting from the fifth to the second cause of infant mortality from 1980 to 2000, thus highlighting the need for specific health policy strategies. Some governmental and nongovernmental actions related to birth defects in Brazil include information services on teratogenic agents and inborn errors of metabolism, monitoring of birth defects, neonatal screening and treatment of some genetic diseases, and rubella immunization. In addition, flour fortification with folic acid for prevention of certain birth defects has begun recently. Despite the importance of such initiatives, it is still difficult to view birth defects from a comprehensive perspective. A specific national policy on birth defects must be formulated. Active participation is needed by the Ministry of Health, using existing genetic services as the backbone, in order to develop a regionalized, hierarchical, and functional network related to birth defects in Brazil
Identification of familial clustering for cancer through the family health strategy program in the municipality of Angra dos Reis, Rio de Janeiro, Brazil
A highly complex rea(2;3;11) and aniridia by position effect
A two-year-old boy presenting with bilateral aniridia and psychomotor retardation had a de novo (2;3;11) highly complex rearrangement which was characterized as far as possible by means of G-banding and FISH assays with multiple probes including cosmids for the Wilms, Aniridia, Genital anomalies and Retardation (WAGR) region, alphoid repeats for chromosomes 2, 3 and 11, subtelomere probes for 2p/2q, 3p/3q and 11q and BACs for 2q32 and 3q13. We identified approximately 15 breakpoints with at least three interchromosomal and three intrachromosome anomalies involving chromosome 11. Both parents had normal karyotypes and no cryptic 11p rearrangements revealed by the chromosome 11 cosmid panel. The lack of a deletion of PAX6 pointed to the direct insertion of an approximately 300-kb segment involving the cosmids FO2121 and AO4160, and more specifically the insertion's proximal breakpoint in the approximately 150-kb segment between FO2121 and FAT5 (PAX6), as the responsible factor for the patient's aniridia via a position effect resulting in functional haploinsufficiency of the PAX6 gene. This case illustrates the importance of recognizing that de novo complex chromosomal rearrangements found in patients with diverse clinical features may contribute to the phenotype, but that multiple mechanisms and higher levels of complexity may be unmasked by high resolution molecular cytogenetic studies
Doença de Hirschsprung: experiência com uma série de 55 casos Hirschsprung's disease: experiment with a serie of 55 cases
OBJETIVOS: analisar aspectos clínicos de pacientes com Doença de Hirschprung (DH). MÉTODOS: realizou-se estudo de caso institucional, retrospectivo, via revisão de prontuários de pacientes com DH atendidos no Instituto Fernandes Figueira entre 1993 e 2003. RESULTADOS: Em um total de 55 pacientes, 98% apresentaram sintomas neonatais, sendo 47,2% diagnosticados nesse período; em 88,9% o enema baritado foi conclusivo; 69% tinham DH de segmento curto; 16,3% síndrome de Down; 15,2% outras anomalias congênitas; 40% foram rastreados para mutações RET associadas a neoplasias endócrinas múltiplas (MEN2A), não sendo detectada nenhuma; 63,6% fizeram abaixamento estagiado do colon/íleo; 12,72% abaixamento endoretal transanal primário; as principais complicações cirúrgicas foram sepse, enterocolite e obstrução intestinal; distúrbios da defecação foram detectados anos pós-cirurgia; a taxa de letalidade foi 9,25%; os óbitos relacionaram-se a enterocolite e sepse pós-operatórias. CONCLUSÃO: embora apresentasse sintomas neonatais, a maioria dos pacientes foi diagnosticada tardiamente. Enterocolite foi a principal causa de morbimortalidade. Distúrbios da defecação ocorrem com frequência, demandando follow-up prolongado. Embora rara, a associação com MEN2A precisa ser investigada devido à agressividade da doença. A heterogeneidade clínica e genética da DH exige atuação de equipe multidisciplinar.<br>OBJECTIVES: to analyze clinical features of patients with Hirschprung's Disease (HD). METHODS: a retrospective institutional case study was carried out using the medical records of patients with HD attending the Fernandes Figueira Institute between 1993 and 2003. RESULTS: out of a total of 55 patients, 98% presented symptoms on birth, 47.2% of whom were diagnosed during the neonatal period; in 88.9% of cases the barium enema was conclusive; 69% had short segment HD; 16.3% Down's Syndrome; 15.2% other congenital anomalies; 40% were screened for RET mutations associated with multiple endocrine neoplasias (MEN2A), although none were detected; 63.6% had staged pull-through surgery on the colon or ileum; 12.72% primary transanal endorectal pull-through surgery; the main complications arising from surgery were sepsis, enterocolitis and obstruction of the intestines; abnormal bowel movements were detected years after the surgery; the mortality rate was 9.25%, the causes of death being post-operal enterocolitis and sepsis. CONCLUSION: although patients presented symptoms on birth, most were diagnosed at a later stage. Enterocolitis was the main cause of death. Abnormal bowel movements frequently occurred, requiring prolonged follow-up. Although rare, the association with MEN2A needs to be investigated owing to the highly aggressive nature of the disease. The clinical and genetic heterogeneity of HD necessitates the involvement of a multidisciplinary team
Farmacogenética de inibidores seletivos de recaptação de serotonina: uma revisão Pharmacogenetics of selective serotonine reuptake inhibitors: a review
A variabilidade da resposta aos medicamentos se deve em grande parte a fatores genéticos, e essa variabilidade afeta os efeitos terapêuticos e as reações adversas, de forma que a mesma dose de um medicamento pode ser benéfica para um paciente mas ineficaz para outro. Os fármacos conhecidos como inibidores seletivos de recaptação de serotonina (ISRSs) pertencem a uma classe de medicamentos utilizados para o tratamento de uma série de patologias relacionadas com a serotonina, especialmente a depressão. O objetivo deste trabalho é reunir os dados presentes na literatura sobre a associação de genes candidatos com a resposta a ISRSs, fornecendo assim um panorama sobre o estado atual de conhecimento sobre o assunto. A resposta ao tratamento com ISRSs depende da variabilidade de genes codificantes de proteínas envolvidas com o papel da serotonina no cérebro. Com os avanços conquistados a partir do Projeto Genoma Humano, foi possível detectar essas variações, e várias delas mostraram ter importância farmacogenética. Portanto, alguns dos genes relacionados à farmacogenética dos ISRSs já são conhecidos, o que torna clara a necessidade de maiores investigações prospectivas para determinar a real utilidade desse conhecimento na prática clínica, com relação à possibilidade da determinação da dose adequada do fármaco correto para cada paciente, prática que vem sendo denominada de "medicina personalizada".<br>A large proportion of the variability in drug response is due to genetic factors, and this variability affects therapeutic effects and adverse reactions, so that the same dosage of a drug can be beneficial to some patients, but ineffective to others. The drugs known as selective serotonin reuptake inhibitors (SSRI) belong to a pharmacological class used in the management of a number of diseases related to serotonin, especially depression. The aim of this paper is to collect data from the literature about the association of candidate genes with response to SSRI, providing an overview on the current knowledge of this subject. The effect of SSRI treatment depends on the variability in genes coding proteins involved with the role of serotonin in the brain. The new data from the Human Genome Project allowed detection of these variations, and several of them proved to have pharmacogenetic importance. Therefore, some of the genes related to SSRI pharmacogenetics are already known. This reinforces the need of larger prospective investigations to determine the real use of this knowledge in clinical practice as to the possibility of determining the right dosage, and the right drug to each patient, a practice that has been called "personalized medicine"