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1.
Med. clín (Ed. impr.) ; 160(1): 1-9, enero 2023. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-213901

RESUMO

Introducción: El tratamiento con estatinas podría presentar un efecto pronóstico beneficioso en pacientes con COVID-19, dadas sus propiedades inmunomoduladoras, antiinflamatorias y estabilizadoras de la placa de ateroma. Nuestro propósito fue analizar esta hipótesis tomando como base el registro de COVID-19 de un hospital universitario español.MétodosRealizamos un estudio observacional y retrospectivo en el que se incluyeron los pacientes hospitalizados con COVID-19 diagnosticado mediante PCR entre marzo de 2020 y octubre de 2020 en un centro. Mediante regresión logística, diseñamos una puntuación de propensión para estimar la probabilidad de que un paciente recibiese tratamiento con estatinas antes del ingreso. Comparamos la supervivencia de los pacientes con y sin tratamiento con estatinas mediante la regresión de Cox ponderada por la inversa de la probabilidad de recibir el tratamiento (IPT). La mediana de seguimiento fue de 406días.ResultadosEstudiamos 1.122 pacientes hospitalizados con COVID-19, cuya mediana de edad era de 71años y de los cuales 488 (43,5%) eran mujeres. 451 (40,2%) pacientes recibían estatinas antes del ingreso. En el análisis de supervivencia ponderado por la IPT, el tratamiento previo con estatinas se asoció a una reducción significativa de la mortalidad (HR: 0,76; IC95%: 0,59-0,97). El mayor beneficio del tratamiento previo con estatinas se observó en los subgrupos de pacientes con enfermedad arterial coronaria (HR: 0,32; IC95%: 0,18-0,56) y enfermedad arterial extracardiaca (HR: 0,45; IC95%: 0,28-0,73).ConclusionesNuestro estudio mostró una asociación significativa entre el tratamiento previo con estatinas y una menor mortalidad en pacientes hospitalizados con COVID-19. El beneficio pronóstico observado fue mayor en los pacientes con enfermedad aterosclerótica coronaria o extracardiaca previa. (AU)


Introduction: Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital.MethodsWe conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days.ResultsWe studied 1122 hospitalized patients with COVID-19, whose median age was 71years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76; 95%CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32; 95%CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45; 95%CI: 0.28-0.73).ConclusionsOur study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease. (AU)


Assuntos
Humanos , Aterosclerose , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Infecções por Coronavirus/epidemiologia , Doença da Artéria Coronariana , Prognóstico , Estudos Retrospectivos
2.
Med Clin (Barc) ; 160(1): 1-9, 2023 01 05.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-35618499

RESUMO

INTRODUCTION: Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital. METHODS: We conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days. RESULTS: We studied 1122 hospitalized patients with COVID-19, whose median age was 71years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76; 95%CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32; 95%CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45; 95%CI: 0.28-0.73). CONCLUSIONS: Our study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease.


Assuntos
Aterosclerose , COVID-19 , Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Feminino , Idoso , Masculino , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Retrospectivos , Prognóstico
3.
Med Clin (Engl Ed) ; 160(1): 1-9, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36504601

RESUMO

Introduction: Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital. Methods: We conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days. Results: We studied 1122 hospitalized patients with COVID-19, whose median age was 71 years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76; 95% CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32; 95% CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45; 95% CI: 0.28-0.73). Conclusions: Our study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease.


Introducción: El tratamiento con estatinas podría presentar un efecto pronóstico beneficioso en pacientes con COVID-19, dadas sus propiedades inmunomoduladoras, antiinflamatorias y estabilizadoras de la placa de ateroma. Nuestro propósito fue analizar esta hipótesis tomando como base el registro de COVID-19 de un hospital universitario español. Métodos: Realizamos un estudio observacional y retrospectivo en el que se incluyeron los pacientes hospitalizados con COVID-19 diagnosticado mediante PCR entre marzo de 2020 y octubre de 2020 en un centro. Mediante regresión logística, diseñamos una puntuación de propensión para estimar la probabilidad de que un paciente recibiese tratamiento con estatinas antes del ingreso. Comparamos la supervivencia de los pacientes con y sin tratamiento con estatinas mediante la regresión de Cox ponderada por la inversa de la probabilidad de recibir el tratamiento (IPT). La mediana de seguimiento fue de 406 días. Resultados: Estudiamos 1.122 pacientes hospitalizados con COVID-19, cuya mediana de edad era de 71 años y de los cuales 488 (43,5%) eran mujeres. 451 (40,2%) pacientes recibían estatinas antes del ingreso. En el análisis de supervivencia ponderado por la IPT, el tratamiento previo con estatinas se asoció a una reducción significativa de la mortalidad (HR: 0,76; IC 95%: 0,59­0,97). El mayor beneficio del tratamiento previo con estatinas se observó en los subgrupos de pacientes con enfermedad arterial coronaria (HR: 0,32; IC 95%: 0,18­0,56) y enfermedad arterial extracardiaca (HR: 0,45; IC 95%: 0,28­0,73). Conclusiones: Nuestro estudio mostró una asociación significativa entre el tratamiento previo con estatinas y una menor mortalidad en pacientes hospitalizados con COVID-19. El beneficio pronóstico observado fue mayor en los pacientes con enfermedad aterosclerótica coronaria o extracardiaca previa.

4.
Pediatr Res ; 94(1): 356-364, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36456690

RESUMO

BACKGROUND: The aim of this study was to determine the extent to which socioeconomic characteristics of the home and neighborhood are associated with racial inequalities in brain outcomes. METHODS: We performed a cross-sectional analysis of the baseline dataset (v.2.0.1) from the Adolescent Brain and Cognitive Development (ABCD) Study. Cognitive performance was assessed using the National Institutes of Health Toolbox (NIH-TB) cognitive battery. Standard socioeconomic indicators of the family and neighborhood were derived from census-related statistics. Cortical morphometric measures included MRI-derived thickness, area, and volume. RESULTS: 9638 children were included. Each NIH-TB cognitive measure was negatively associated with household and neighborhood socioeconomic characteristics. Differences in cognitive scores between Black or Hispanic children and other racial groups were mitigated by higher household income. Most children from lowest-income families or residents in impoverished neighborhoods were Black or Hispanic. These disparities were associated with racial differences in NIH-TB measures and mediated by smaller cortical brain volumes. CONCLUSIONS: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children. IMPACT: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these disparities related to socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children.


Assuntos
Pobreza , Grupos Raciais , Criança , Adolescente , Humanos , Estudos Transversais , Fatores Socioeconômicos , Características de Residência , Encéfalo/diagnóstico por imagem
5.
Open Respir Arch ; 3(3): 100104, 2021.
Artigo em Espanhol | MEDLINE | ID: mdl-37496773

RESUMO

Objectives: In 2011, only 18% of the population in Galician knew the COPD. Since then, activities have been carried out to publicize this disease. The objective of this study was to evaluate the current situation regarding the knowledge of COPD in the Galician population. Methodology: Cross-sectional study, through telephone surveys. Variables included in the questionnaire, related to knowledge of the disease, were analyzed. Results: 872 respondents, 53% women, mean age 54 years. 63% with secondary/university studies. 40% has knowledge of COPD. In contrast, more than 90% of respondents know other high-frequency diseases (diabetes, stroke, asthma). The factors most associated with knowledge of COPD were female gender, having secondary/university studies, and having previously performed spirometry. Conclusions: The knowledge of COPD in the Galician population is 40% now, higher than in 2011, but it is far from that of other prevalent diseases.

6.
Rev. colomb. anestesiol ; 48(2): 91-95, Jan.-June 2020. graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1115562

RESUMO

Abstract Submental intubation (SMI) is useful in surgical procedures where nasotracheal intubation is contraindicated and orotracheal intubation is not ideal, making it an alternative to tracheostomy since it is performed in less time, with less morbidity and mortality, minimal postoperatory care, as well as an aesthetically acceptable scar. We present 2 cases of pediatric patients with a successful SMI. In addition, we briefly review current literature regarding pediatric population.


Resumen La intubación submentoniana (ISM) es útil en procedimientos quirúrgicos en donde la intubación nasotraqueal está contra indicada y la intubación orotraqueal no es ideal, siendo así una alternativa a la traqueostomía, ya que se realiza en menor tiempo, con menor morbimortalidad y mínimos cuidados posoperatorios, y con una cicatriz estéticamente aceptable. Se presentan dos casos de pacientes pediátricos en los cuales la ISM fue exitosa y se revisa de forma breve la literatura relacionada en población infantil.


Assuntos
Humanos , Feminino , Criança , Adolescente , Intubação , Intubação Intratraqueal , Cirurgia Bucal , Forame Mentual
8.
Arch. bronconeumol. (Ed. impr.) ; 55(6): 312-318, jun. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-181766

RESUMO

Introducción y objetivos: Los determinantes en fases iniciales de la historia natural de la enfermedad pulmonar obstructiva crónica (EPOC) son poco conocidos. Entenderlos mejor es de capital importancia para poder diseñar intervenciones dirigidas a modificar su pronóstico. Los principales objetivos del estudio son: a) caracterizar a una población de adultos jóvenes con EPOC de forma multidimensional; b) comparar estos pacientes con sujetos fumadores con función pulmonar normal; y c) establecer una cohorte de adultos jóvenes con y sin EPOC, que pueda ser seguida a largo plazo para conocer mejor la historia natural de la enfermedad. Participantes y método: EARLY COPD es un estudio multicéntrico de casos y controles que permitirá establecer una cohorte de sujetos para su seguimiento posterior. Se seleccionaron 311 (101 casos y 210 controles) participantes reclutados en una treintena de centros de atención primaria y 12 hospitales de 8 comunidades autónomas españolas. Los participantes eran fumadores o exfumadores (>10 paquetes año) de entre 35-50 años de edad. Los casos presentaban una espirometría obstructiva con un FEV1/FVC<70% y los controles una espirometría normal con un FEV1/FVC≥70%. Las principales variables de estudio que se han determinado son las siguientes: cuestionarios de salud, síntomas, exacerbaciones y actividad física, pruebas de función respiratoria, análisis biológicos de sangre y esputo y TAC de baja radiación. Para el análisis estadístico de los resultados se describirán las características de los pacientes con EPOC y se compararán con los sujetos del grupo control mediante un modelo de regresión logística


Introduction and objectives: Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis. Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function; and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease. Participants and method: This is a case-control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up. A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (>10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC<70%. The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Progressão da Doença , Tabagismo/complicações , Estudos de Casos e Controles , Seguimentos , Estudos Longitudinais
10.
Protein Sci ; 28(1): 90-99, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098072

RESUMO

Siderophore A (SidA) from Aspergillus fumigatus is a flavin-containing monooxygenase that hydroxylates ornithine (Orn) at the amino group of the side chain. Lysine (Lys) also binds to the active site of SidA; however, hydroxylation is not efficient and H2 O2 is the main product. The effect of pH on steady-state kinetic parameters was measured and the results were consistent with Orn binding with the side chain amino group in the neutral form. From the pH dependence on flavin oxidation in the absence of Orn, a pKa value >9 was determined and assigned to the FAD-N5 atom. In the presence of Orn, the pH dependence displayed a pKa value of 6.7 ±0.1 and of 7.70 ±0.10 in the presence of Lys. Q102 interacts with NADPH and, upon mutation to alanine, leads to destabilization of the C4a-hydroperoxyflavin (FADOOH ). Flavin oxidation with Q102A showed a pKa value of ~8.0. The data are consistent with the pKa of the FAD N5-atom being modulated to a value >9 in the absence of Orn, which aids in the stabilization of FADOOH . Changes in the FAD-N5 environment lead to a decrease in the pKa value, which facilitates elimination of H2 O2 or H2 O. These findings are supported by solvent kinetic isotope effect experiments, which show that proton transfer from the FAD N5-atom is rate limiting in the absence of a substrate, however, is significantly less rate limiting in the presence of Orn and or Lys.


Assuntos
Aspergillus fumigatus/enzimologia , Flavina-Adenina Dinucleotídeo/química , Proteínas Fúngicas/química , Oxigenases de Função Mista/química , Sideróforos/química , Oxirredução
11.
Arch Bronconeumol (Engl Ed) ; 55(6): 312-318, 2019 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30429076

RESUMO

INTRODUCTION AND OBJECTIVES: Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis. Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function; and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease. PARTICIPANTS AND METHOD: This is a case-control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up. A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (>10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC<70%. The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Idade de Início , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Progressão da Doença , Exercício Físico , Feminino , Seguimentos , Volume Expiratório Forçado , Estudo de Associação Genômica Ampla , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Projetos de Pesquisa , Fumantes , Abandono do Hábito de Fumar , Espanha/epidemiologia , Escarro/microbiologia , Tomografia Computadorizada por Raios X , Capacidade Vital
12.
Arch Biochem Biophys ; 585: 25-31, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26375201

RESUMO

The SidA ornithine N5-monooxygenase from Aspergillus fumigatus is a flavin monooxygenase that catalyzes the NADPH-dependent hydroxylation of ornithine. Herein we report a mutagenesis study targeting four residues that contact ornithine in crystal structures of SidA: Lys107, Asn293, Asn323, and Ser469. Mutation of Lys107 to Ala abolishes activity as measured in steady-state oxygen consumption and ornithine hydroxylation assays, indicating that the ionic interaction of Lys107 with the carboxylate of ornithine is essential for catalysis. Mutation of Asn293, Asn323, or Ser469 individually to Ala results in >14-fold increases in Km values for ornithine. Asn323 to Ala also increases the rate constant for flavin reduction by NADPH by 18-fold. Asn323 is unique among the four ornithine binding residues in that it also interacts with NADPH by forming a hydrogen bond with the nicotinamide ribose. The crystal structure of N323A complexed with NADP(+) and ornithine shows that the nicontinamide riboside group of NADP is disordered. This result suggests that the increase in flavin reduction rate results from an increase in conformational space available to the enzyme-bound NADP(H). Asn323 thus facilitates ornithine binding at the expense of hindering flavin reduction, which demonstrates the delicate balance that exists within protein-ligand interaction networks in enzyme active sites.


Assuntos
Aspergillus fumigatus/química , Flavinas/química , Proteínas Fúngicas/química , Oxigenases de Função Mista/química , NADP/química , Ornitina/química , Aspergillus fumigatus/enzimologia , Biocatálise , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Fúngicas/genética , Expressão Gênica , Ligação de Hidrogênio , Hidroxilação , Cinética , Oxigenases de Função Mista/genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Oxirredução , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Especificidade por Substrato
13.
J Biol Chem ; 290(20): 12676-88, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25802330

RESUMO

N-Hydroxylating monooxygenases are involved in the biosynthesis of iron-chelating hydroxamate-containing siderophores that play a role in microbial virulence. These flavoenzymes catalyze the NADPH- and oxygen-dependent hydroxylation of amines such as those found on the side chains of lysine and ornithine. In this work we report the biochemical and structural characterization of Nocardia farcinica Lys monooxygenase (NbtG), which has similar biochemical properties to mycobacterial homologs. NbtG is also active on d-Lys, although it binds l-Lys with a higher affinity. Differently from the ornithine monooxygenases PvdA, SidA, and KtzI, NbtG can use both NADH and NADPH and is highly uncoupled, producing more superoxide and hydrogen peroxide than hydroxylated Lys. The crystal structure of NbtG solved at 2.4 Å resolution revealed an unexpected protein conformation with a 30° rotation of the NAD(P)H domain with respect to the flavin adenine dinucleotide (FAD) domain that precludes binding of the nicotinamide cofactor. This "occluded" structure may explain the biochemical properties of NbtG, specifically with regard to the substantial uncoupling and limited stabilization of the C4a-hydroperoxyflavin intermediate. Biological implications of these findings are discussed.


Assuntos
Proteínas de Bactérias , Lisina , Oxigenases de Função Mista , Nocardia/enzimologia , Consumo de Oxigênio/fisiologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Flavina-Adenina Dinucleotídeo/química , Flavina-Adenina Dinucleotídeo/genética , Flavina-Adenina Dinucleotídeo/metabolismo , Hidroxilação , Lisina/química , Lisina/genética , Lisina/metabolismo , Oxigenases de Função Mista/química , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , NADP/química , NADP/genética , NADP/metabolismo , Nocardia/genética , Estrutura Terciária de Proteína
14.
Arch Biochem Biophys ; 550-551: 58-66, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24769337

RESUMO

The mechanism of Mycobacterium smegmatis G (MbsG), a flavin-dependent l-lysine monooxygenase, was investigated under steady-state and rapid reaction conditions using primary and solvent kinetic isotope effects, substrate analogs, pH and solvent viscosity effects as mechanistic probes. The results suggest that l-lysine binds before NAD(P)H, which leads to a decrease in the rate constant for flavin reduction. l-lysine binding has no effect on the rate of flavin oxidation, which occurs in a one-step process without the observation of a C4a-hydroperoxyflavin intermediate. Similar effects were determined with several substrate analogs. Flavin oxidation is pH independent while the kcat/Km and kred/KD pH profiles for NAD(P)H exhibit single pKa values of ∼6.0, with increasing activity as the pH decreases. At lower pH, the enzyme becomes more uncoupled, producing more hydrogen peroxide and superoxide. Hydride transfer is partially rate-limiting at neutral pH and becomes more rate-limiting at low pH. An inverse solvent viscosity effect on kcat/Km for NAD(P)H was observed at neutral pH whereas a normal solvent viscosity effect was observed at lower pH. Together, the results indicate a unique mechanism where a rate-limiting and pH-sensitive conformational change occurs in the reductive half-reaction, which affects the efficiency of lysine hydroxylation.


Assuntos
Proteínas de Bactérias/metabolismo , Dinitrocresóis/metabolismo , Lisina/metabolismo , Oxigenases de Função Mista/metabolismo , Mycobacterium smegmatis/química , NADP/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Biocatálise , Flavinas , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Cinética , Oxigenases de Função Mista/química , Oxigenases de Função Mista/genética , Mycobacterium smegmatis/enzimologia , Oxirredução , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Superóxidos/metabolismo
15.
Biochim Biophys Acta ; 1844(4): 778-84, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24534646

RESUMO

Siderophore A (SidA) is a flavin-dependent monooxygenase that catalyzes the NAD(P)H- and oxygen-dependent hydroxylation of ornithine in the biosynthesis of siderophores in Aspergillus fumigatus and is essential for virulence. SidA can utilize both NADPH or NADH for activity; however, the enzyme is selective for NADPH. Structural analysis shows that R279 interacts with the 2'-phosphate of NADPH. To probe the role of electrostatic interactions in coenzyme selectivity, R279 was mutated to both an alanine and a glutamate. The mutant proteins were active but highly uncoupled, oxidizing NADPH and producing hydrogen peroxide instead of hydroxylated ornithine. For wtSidA, the catalytic efficiency was 6-fold higher with NADPH as compared to NADH. For the R279A mutant the catalytic efficiency was the same with both coenyzmes, while for the R279E mutant the catalytic efficiency was 5-fold higher with NADH. The effects are mainly due to an increase in the KD values, as no major changes on the kcat or flavin reduction values were observed. Thus, the absence of a positive charge leads to no coenzyme selectivity while introduction of a negative charge leads to preference for NADH. Flavin fluorescence studies suggest altered interaction between the flavin and NADP⁺ in the mutant enzymes. The effects are caused by different binding modes of the coenzyme upon removal of the positive charge at position 279, as no major conformational changes were observed in the structure for R279A. The results indicate that the positive charge at position 279 is critical for tight binding of NADPH and efficient hydroxylation.


Assuntos
Arginina/química , Aspergillus fumigatus/química , Flavinas/química , Proteínas Fúngicas/química , Oxigenases de Função Mista/química , NADP/química , Ornitina/química , Alanina/química , Alanina/metabolismo , Arginina/metabolismo , Aspergillus fumigatus/enzimologia , Aspergillus fumigatus/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Flavinas/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Hidroxilação , Cinética , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , NAD/química , NAD/metabolismo , NADP/metabolismo , Ornitina/metabolismo , Oxirredução , Oxigênio/química , Oxigênio/metabolismo , Conformação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Eletricidade Estática , Especificidade por Substrato
18.
Gastroenterol. hepatol. (Ed. impr.) ; 33(1): 25-29, ener. 2010. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-80376

RESUMO

Presentamos el caso de una paciente con síntomas dispépticos típicos, poco llamativos inicialmente, a la que se diagnosticó, tras realizar un estudio adecuado, de una tumoración retroperitoneal de gran tamaño.Discutiremos la aproximación diágnostica y revisaremos la bibliografía existente sobre esta enfermedad


Dyspepsia is a frequent cause of referral to gastroenterology units. After appropriate investigations, many patients receive a diagnosis of functional disorders, although dyspepsia can have an organic basis.We present the case of a woman with typical symptoms of dyspepsia, which were initially mild. After appropriate investigations, the patient was diagnosed with a giant retroperitoneal tumor. We discuss the diagnostic approach to this entity and review the literature on the topic


Assuntos
Humanos , Feminino , Adulto , Cisto Mesentérico/diagnóstico , Dispepsia/etiologia , Cisto Mesentérico/complicações , Espaço Retroperitoneal
19.
Gastroenterol Hepatol ; 33(1): 25-9, 2010 Jan.
Artigo em Espanhol | MEDLINE | ID: mdl-19800147

RESUMO

Dyspepsia is a frequent cause of referral to gastroenterology units. After appropriate investigations, many patients receive a diagnosis of functional disorders, although dyspepsia can have an organic basis. We present the case of a woman with typical symptoms of dyspepsia, which were initially mild. After appropriate investigations, the patient was diagnosed with a giant retroperitoneal tumor. We discuss the diagnostic approach to this entity and review the literature on the topic.


Assuntos
Cisto Mesentérico/diagnóstico , Adulto , Dispepsia/etiologia , Feminino , Humanos , Cisto Mesentérico/complicações , Espaço Retroperitoneal
20.
Gastroenterol. hepatol. (Ed. impr.) ; 32(8): 552-556, oct. 2009. ilus
Artigo em Espanhol | IBECS | ID: ibc-72827

RESUMO

La ingesta de cuerpos extraños representa la segunda indicación en frecuencia para la realización de una endoscopia digestiva alta urgente. Una vez que pasan al estómago suelen expulsarse de forma espontánea, si bien un porcentaje bajo de éstos queda enclavado en la mucosa gastrointestinal por ser afilados o de gran tamaño.Las espinas de pescado son un importante número de los cuerpos extraños ingeridos.Se presentan 2 casos en que la ingesta de una espina de pescado produjo una perforación gástrica que se resolvió satisfactoriamente de forma endoscópica.La perforación se considera una contraindicación absoluta para realizar endoscopias, tanto altas como bajas, si bien casos como éstos enseñan a individualizar siempre la decisión de realizar tratamientos endoscópicos, ya que perforaciones puntiformes, sobre todo si se asocian a reacción inflamatoria parietal y peritoneal que ayude a cerrar la perforación de forma espontánea, pueden tratarse sin recurrir a cirugía(AU)


Intake of foreign bodies is the second most frequent indication for urgent upper gastrointestinal endoscopy. Once in the stomach, foreign bodies are usually spontaneously eliminated. However, a small percentage of large or sharp objects become stuck in the gastrointestinal mucosa.Fish bones represent a substantial number of ingested foreign bodies. We present two cases of fish bone intake producing gastric perforation satisfactorily resolved with endoscopy.Perforation is considered an absolute spcontraindication for upper and lower gastrointestinal endoscopy. Cases such as those reported herein indicate that the decision to perform endoscopic treatment should always be individualized since punctiform perforations – especially if associated with a parietal and peritoneal inflammatory reaction that helps to close the perforation spontaneously – can be treated non-surgically(AU)


Assuntos
Humanos , Masculino , Feminino , Idoso , Estômago/lesões , Corpos Estranhos/complicações , Ruptura Gástrica/etiologia , Endoscopia Gastrointestinal
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