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BACKGROUND: The relationship between obesity and risk of complications described during the 2009 influenza pandemic is poorly defined for seasonal influenza and other viral causes of influenza-like illness (ILI). METHODS: An observational cohort of hospitalized and outpatient participants with ILI was conducted in six hospitals in Mexico. Nasopharyngeal swabs were tested for influenza and other common respiratory pathogens. RESULTS: A total of 4778 participants were enrolled in this study and had complete data. A total of 2053 (43.0%) had severe ILI. Seven hundred and seventy-eight (16.3%) were positive for influenza, 2636 (55.2%) were positive for other viral respiratory pathogens, and 1364 (28.5%) had no respiratory virus isolated. Adults with influenza were more likely to be hospitalized if they were underweight (OR: 5.20), obese (OR: 3.18), or morbidly obese (OR: 18.40) compared to normal-weight adults. Obese adults with H1N1 had a sixfold increase in odds of hospitalization over H3N2 and B (obese OR: 8.96 vs 1.35, morbidly obese OR: 35.13 vs 5.58, respectively) compared to normal-weight adults. In adults with coronavirus, metapneumovirus, parainfluenza, and rhinovirus, participants that were underweight (OR: 4.07) and morbidly obese (OR: 2.78) were more likely to be hospitalized as compared to normal-weight adults. All-cause influenza-like illness had a similar but less pronounced association between underweight or morbidly obesity and hospitalization. CONCLUSIONS: There is an increased risk of being hospitalized in adult participants that are underweight or morbidly obese, regardless of their viral pathogen status. Having influenza, however, significantly increases the odds of hospitalization in those who are underweight or morbidly obese.
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Influenza Humana/complicações , Obesidade/complicações , Sobrepeso/complicações , Infecções Respiratórias/complicações , Magreza/complicações , Adulto , Idoso , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hospitalização , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Obesidade Mórbida/complicações , Pacientes Ambulatoriais , Infecções Respiratórias/virologia , Fatores de RiscoRESUMO
This article was migrated. The article was marked as recommended. Few longitudinal integrated clerkships (LICs) have increased the proportion of students who choose to go into primary care or work with underserved populations. A mixed-methods questionnaire was developed and sent to alumni (2006-2016) of the Interclerkship Ambulatory Care Tract (InterACT), a third-year clerkship in which students apply evidence-based medicine and chronic care model principles to outpatient longitudinal care. A likert scale was utilized for quantitative questions. Descriptive and thematic analyses were performed on the qualitative responses using a constant comparative approach. A majority (80%; 49/61) responded. Of the 44 physicians who responded to questions about current specialty, 75% indicated pediatrics, family medicine, or internal medicine. The majority of respondents (89%) reported that they care for patients considered to be medically underserved. Alumni overwhelmingly felt that the clerkship impacted the following: their specialty choice (71%, 34/48), and the population of patients they chose to take care of (80%, 39/49). The following attributes emerged from the qualitative questions as key determinants of future decisions regarding specialty and patient population: holistic patient care, strong mentorship, longitudinal patient relationships, and care of the homebound. These key attributes, if implemented in other LICs, may be a means to increase the number of medical students that choose to work in primary care fields and/or with underserved populations.
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Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly disorder resulting from mutations in genes that encode the core components of the cohesin complex, SMC1A, SMC3, and RAD21, or two of its regulatory proteins, NIPBL and HDAC8. HDAC8 is the human SMC3 lysine deacetylase required for cohesin recycling in the cell cycle. To date, 16 different missense mutations in HDAC8 have recently been identified in children diagnosed with CdLS. To understand the molecular effects of these mutations in causing CdLS and overlapping phenotypes, we have fully characterized the structure and function of five HDAC8 mutants: C153F, A188T, I243N, T311M, and H334R. X-ray crystal structures reveal that each mutation causes local structural changes that compromise catalysis and/or thermostability. For example, the C153F mutation triggers conformational changes that block acetate product release channels, resulting in only 2% residual catalytic activity. In contrast, the H334R mutation causes structural changes in a polypeptide loop distant from the active site and results in 91% residual activity, but the thermostability of this mutant is significantly compromised. Strikingly, the catalytic activity of these mutants can be partially or fully rescued in vitro by the HDAC8 activator N-(phenylcarbamothioyl)benzamide. These results suggest that HDAC8 activators might be useful leads in the search for new therapeutic strategies in managing CdLS.
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Histona Desacetilases/química , Histona Desacetilases/genética , Mutação , Proteínas Repressoras/química , Proteínas Repressoras/genética , Benzamidas/farmacologia , Catálise , Domínio Catalítico , Cristalografia por Raios X , Síndrome de Cornélia de Lange , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Feniltioureia/análogos & derivados , Feniltioureia/farmacologia , Conformação Proteica , Estabilidade Proteica , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-AtividadeRESUMO
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for â¼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
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Fontanelas Cranianas/anormalidades , Síndrome de Cornélia de Lange/enzimologia , Anormalidades do Olho/enzimologia , Genes Ligados ao Cromossomo X , Histona Desacetilases/genética , Hipertelorismo/enzimologia , Proteínas Repressoras/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Fontanelas Cranianas/enzimologia , Síndrome de Cornélia de Lange/genética , Anormalidades do Olho/genética , Feminino , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Hipertelorismo/genética , Lactente , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Fenótipo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Alinhamento de SequênciaRESUMO
The reversible acetylation of lysine to form N6-acetyllysine in the regulation of protein function is a hallmark of epigenetics. Acetylation of the positively charged amino group of the lysine side chain generates a neutral N-alkylacetamide moiety that serves as a molecular "switch" for the modulation of protein function and protein-protein interactions. We now report the analysis of 381 N6-acetyllysine side chain amide conformations as found in 79 protein crystal structures and 11 protein NMR structures deposited in the Protein Data Bank (PDB) of the Research Collaboratory for Structural Bioinformatics. We find that only 74.3% of N6-acetyllysine residues in protein crystal structures and 46.5% in protein NMR structures contain amide groups with energetically preferred trans or generously trans conformations. Surprisingly, 17.6% of N6-acetyllysine residues in protein crystal structures and 5.3% in protein NMR structures contain amide groups with energetically unfavorable cis or generously cis conformations. Even more surprisingly, 8.1% of N6-acetyllysine residues in protein crystal structures and 48.2% in NMR structures contain amide groups with energetically prohibitive twisted conformations that approach the transition state structure for cis-trans isomerization. In contrast, 109 unique N-alkylacetamide groups contained in 84 highly accurate small molecule crystal structures retrieved from the Cambridge Structural Database exclusively adopt energetically preferred trans conformations. Therefore, we conclude that cis and twisted N6-acetyllysine amides in protein structures deposited in the PDB are erroneously modeled due to their energetically unfavorable or prohibitive conformations.