RESUMO
PURPOSE: Among the inheritable forms of impaired sensitivity to thyroid hormone, resistance to thyroid hormone (RTH) due to mutations in the thyroid hormone receptor beta gene (THRB) is the first and best known described defect, revealing a wide phenotypic variability with an incompletely understood physiopathology. The objective of this study was to evaluate two novel mutations in THRB, N331H and L346R, in an attempt to provide a rational understanding of the harmful effects caused by them. METHODS: The mutations of two patients with RTHß were reproduced for analysis of gene transactivation by dual-luciferase reporter assay, and for molecular modeling for crystallography-based structural assessment. Serum measurements of TSH and FT4 were performed to compare the thyrotrophic resistance to thyroid hormone between RTHß patients and controls. RESULTS: Both mutants showed impaired gene transactivation, with greater damage in L346R. Molecular modeling suggested that the damage occurring in N331H is primarily due to reduced strength of the hydrogen bonds that stabilize T3 in its ligand-binding cavity (LBC), whereas in L346R, the damage is more marked and is mainly due to changes in hydrophobicity and molecular volume inside the LBC. Hormonal dosages indicated that the L346R mutant exhibited greater thyrotrophic resistance than N331H. CONCLUSIONS: This study provides a rational understanding of the effects of mutations, indicating deleterious structural changes in the LBC in both THR, and discloses that not only the position of the mutation but, notably, the nature of the amino acid exchange, has a cardinal role in the functional damage of the receptor.
Assuntos
Receptores beta dos Hormônios Tireóideos , Síndrome da Resistência aos Hormônios Tireóideos , Humanos , Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios TireóideosRESUMO
This study evaluated the profile of patients submitted to gastroplasty in the University Hospital of Maringá during 2008-2009. Clinical charts were analyzed to obtain clinical and laboratory data of all patients with morbid obesity submitted to gastroplasty. During the study period, 28 surgeries were performed, 57% of the patients lived in Maringá, 82% female, 40 years average age, with mean body mass index (BMI) of 46.7kg m-2. It was verified that 39% of the patients maintained an usual non-hypocaloric diet, 25% had quoted dietary reeducation, 36% were sedentary, and 29% practiced some physical activity, and remaining 1/3 of patients presented no data about lifestyle. Regarding associated pathologies, 79% were hypertensive, and 71% of patients presented fasting glucose above 100 mg dL-1, but only 12 of them had diagnosis of Type 2 diabetes mellitus. The hospital stay length was 4 days for 89% of the patients, and 11% had surgery complications. In this group of subjects, there was a clear preponderance of females and high prevalence of other pathologies. Identifying the profile of obese patients contributes to more effective decision-making and emphasizes the crucial role of multidisciplinary approach to health promotion and prevention of early and late complications of morbid obesity and gastroplasty.
Conhecer o perfil dos pacientes submetidos à gastroplastia no Hospital Universitário de Maringá no período de 2008-2009. Foram analisados os prontuários verificando os dados clínicos e laboratoriais de todos os pacientes com obesidade mórbida submetidos à gastroplastia neste período. Foram realizadas 28 cirurgias, 57% dos pacientes eram residentes no município de Maringá, 82% eram do sexo feminino, a idade média foi de 40 anos e a média do índice de massa corporal foi de 46,7 kg m-2. Observou-se que 39% dos pacientes mantinham dieta habitual e não hipocalórica, 25% citaram re-educação alimentar, 29% realizavam atividade física e 36% eram sedentários, os demais pacientes não apresentavam estes dados. Em relação às doenças associadas, 79% eram hipertensos e 71% pacientes apresentavam glicemia de jejum maior que 100 mg dL-1, mas somente 12 deles referiam diagnóstico de diabetes mellitus do Tipo 2. Em 89% dos pacientes, o período de internação foi de quatro dias e 11% tiveram complicações após a cirurgia. Nos pacientes com obesidade mórbida submetidos à gastroplastia, houve predomínio do sexo feminino e alta prevalência de comorbidades. Identificar o perfil destes pacientes contribui para a tomada de decisões e reforça a importância da equipe multidisciplinar na promoção à saúde e prevenção de complicações imediatas e tardias da obesidade mórbida e gastroplastia.