RESUMO
We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking.
Assuntos
Inibidores de Cisteína Proteinase , Simulação de Dinâmica Molecular , Catálise , Catepsina K/metabolismo , Inibidores de Cisteína Proteinase/química , Inibidores de Proteases , Teoria QuânticaRESUMO
OBJECTIVE: To analyze the impact of different classes of lupus nephritis as risk variables for maternal and fetal adverse outcomes in a cohort of pregnant lupus patients. METHODS: This is a cohort study with retrospective and prospective data collection, conducted at the University Hospital of State University of Rio de Janeiro, Brazil, from 2011 to 2016. A total of 147 pregnancies of 137 systemic lupus erythematosus patients of whom 66 had lupus nephritis were included. Demographic and clinical features, as well as maternal and fetal outcomes were observed for each nephritis histological class among systemic lupus erythematosus patients and compared with those without nephritis. Categorical variables were expressed as absolute and relative frequencies and numerical variables as means and standard deviation. The chi-square test with Fisher's correction and Student's t-test were used for statistical analysis. A pvalue < 0.05 was considered statistically significant. RESULTS: Systemic lupus erythematosus patients with proliferative nephritis (classes III/IV, n = 54) presented more frequent disease flares ( p = 0.02), continuous active disease during pregnancy and puerperium ( p = 0.006), hospitalization due to systemic lupus erythematosus ( p < 0.001), hospitalization not directly associated to systemic lupus erythematosus ( p = 0.04), higher frequency of cesarean delivery ( p = 0.03) and preeclampsia ( p = 0.01) than patients without nephritis. Permanent damage measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was more frequent in classes III/IV than among the other patients. The frequency of adverse fetal outcomes such as prematurity and admission to neonatal intensive care unit were not different among systemic lupus erythematosus patients with or without nephritis. However, perinatal deaths were more frequent in patients with all classes of nephritis ( p = 0.003). CONCLUSION: Systemic lupus erythematosus patients with proliferative nephritis (classes III/IV) have a higher frequency of adverse maternal outcomes. This is probably due to the major impact of proliferative forms of nephritis on women's global heath, which is corroborated by the higher Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index findings, although we cannot exclude the negative influence of disease activity for the maternal adverse events. The findings indicate a need for further lupus nephritis classification beyond the nonspecific term nephritis in the context of lupus pregnancy as the impact on maternal and fetal outcomes varies according to histological class.
Assuntos
Nefrite Lúpica/classificação , Nefrite Lúpica/epidemiologia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Adulto , Brasil/epidemiologia , Cesárea/estatística & dados numéricos , Estudos de Coortes , Feminino , Hospitalização/estatística & dados numéricos , Hospitais Universitários , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Terapia Intensiva Neonatal/estatística & dados numéricos , Morte Perinatal , Pré-Eclâmpsia/epidemiologia , Gravidez , Adulto JovemRESUMO
OBJECTIVE: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. DESIGN: Retrospective study. SETTING: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. POPULATION: Women with Ob-APS. METHODS: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). MAIN OUTCOME MEASURES: Risk factors for thrombosis and aGAPSS. RESULTS: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]. CONCLUSION: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. TWEETABLE ABSTRACT: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.
Assuntos
Síndrome Antifosfolipídica/complicações , Complicações Cardiovasculares na Gravidez/imunologia , Trombose/imunologia , Adulto , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/sangue , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Feminino , Humanos , Gravidez , Sistema de Registros , Estudos Retrospectivos , Fatores de RiscoRESUMO
This study analyzed maternal and fetal outcomes of pregnancies of neuropsychiatric systemic lupus erythematosus patients followed in a reference unit. This retrospective cohort study included 26 pregnancies of patients seen between 2011 and 2015 included with history and/or active neuropsychiatric systemic lupus erythematosus among 135 pregnancies. Three patients had active neuropsychiatric systemic lupus erythematosus at conception, but only one remained with neurological activity during gestation, characteristically related to the inadvertent suspension of medications. Twenty six percent of the newborns were small for gestational age and 40% of live births were premature, with no neonatal death or early complications of prematurity. Preeclampsia was diagnosed in nine pregnancies, with two cases of early severe form that resulted in intrauterine fetal death. Patients with neuropsychiatric systemic lupus erythematosus had more prematurity and preeclampsia compared to patients without neuropsychiatric disease. However, when concomitant lupus nephritis was excluded, the gestational results of neuropsychiatric systemic lupus erythematosus patients were more favorable.
Assuntos
Nefrite Lúpica/epidemiologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Pré-Eclâmpsia/epidemiologia , Complicações na Gravidez/epidemiologia , Adulto , Feminino , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Gravidez , Complicações na Gravidez/classificação , Nascimento Prematuro/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Natimorto/epidemiologia , Adulto JovemAssuntos
Cesárea , Política de Saúde , Cobertura do Seguro , Seguro Saúde , Complicações na Gravidez/economia , Opinião Pública , Procedimentos Desnecessários/tendências , Analgesia Obstétrica/estatística & dados numéricos , Brasil/epidemiologia , Cesárea/economia , Cesárea/psicologia , Cesárea/estatística & dados numéricos , Cesárea/tendências , Feminino , Política de Saúde/legislação & jurisprudência , Política de Saúde/tendências , Hospitais Privados , Hospitais Públicos , Humanos , Parto , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Satisfação do Paciente/estatística & dados numéricos , Transferência de Pacientes/tendências , Gravidez , Complicações na Gravidez/diagnóstico , Resultado da Gravidez , Fatores Socioeconômicos , Esterilização Tubária/estatística & dados numéricosRESUMO
Pre-eclampsia (PE) is a major cause of maternal mortality and morbidity, perinatal deaths, preterm birth and intrauterine growth restriction. Differential diagnosis with antiphospholipid syndrome (APS) nephropathy and systemic lupus erythematosus (SLE) nephritis during pregnancy is difficult, if not sometimes impossible, as all three diseases may present hypertension and proteinuria. Improvement in diagnosis of PE has also offered new paths for differential diagnosis with other conditions and the analysis of angiogenic (vascular endothelial growth factor, placental growth factor) and antiangiogenic factors (serum soluble fms-like tyrosine kinase 1, soluble endoglin) is promising for differentiation between PE, APS nephropathy and SLE nephritis. This article reviews published studies about those factors in non-pregnant and pregnant patients with APS and SLE, comparing with patterns described in PE.
Assuntos
Síndrome Antifosfolipídica/complicações , Nefropatias/diagnóstico , Nefrite Lúpica/diagnóstico , Proteínas de Membrana/sangue , Pré-Eclâmpsia/diagnóstico , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Antígenos CD/sangue , Síndrome Antifosfolipídica/sangue , Diagnóstico Diferencial , Endoglina , Feminino , Humanos , Nefropatias/sangue , Nefrite Lúpica/sangue , Pré-Eclâmpsia/sangue , Gravidez , Receptores de Superfície Celular/sangueRESUMO
Mycosis fungoides is the most common disease of the primary cutaneous T-cell lymphoma group. This is a retrospective study to evaluate the outcome of 30 patients with mycosis fungoides who were followed up for at least 3 years, 18 of them followed for 5 years and 9 of them followed for 7 years. A total of 10 patients achieved a sustained remission, 2 patients achieved a remission but then relapsed and three patients died from lymphoma-related death. It is concluded that the majority of the patients with T1 or T2 stage MF usually have a good prognosis. As a rule, those who do progress further in the disease have advanced stages at the moment of the diagnosis; the disease progression occurring during the first 3-5 years after diagnosis.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide , Neoplasias Cutâneas , Seguimentos , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Estadiamento de Neoplasias , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Estudos RetrospectivosRESUMO
Traça a trajetória da ABEn-AL e sua influência na organizaçäo da enfermagem no estado, já que foi fundada muito antes de haver curso de graduaçäo em enfermagem em Alagoas e antes da existência de qualquer outra entidade de classe, constituindo-se assim um marco decisivo tanto na organizaçäo como no desencadeamento das lutas da categoria no Estado de Alagoas (AU)
Assuntos
Sociedades , História da Enfermagem , BrasilRESUMO
Este artigo traça a trajetória da ABEn-AL e sua influência na organização da enfermagem no estado, já que foi fundada muito antes de haver curso de graduação em enfermagem em Alagoas e antes da existência de qualquer outra entidade de classe, constituindo-se assim um marco decisivo tanto na organização como no desencadeamento das lutas da categoria no Estado de Alagoas