RESUMO
To maintain patient flow during the COVID-19 pandemic, rapid and accurate decisions for the safe triage of geriatrics patients was essential as turnaround times for laboratory testing was ineffective at supporting rapid clinical decision-making for transfer of care. Thus, to mitigate and inform these clinical decisions, a quality improvement collaborative project with the geriatrics and virology department was conducted at the Frailty Assessment Unit (FAU) at Aberdeen Royal Infirmary. The goal was to facilitate patient triage during transfer of care with the introduction of Point of Care testing (POCT). The interventions which resulted in significant improvements were based on the fishbone problem solving approach and the driver diagram with change ideas informing the five Plan, Do, Study and Act (PDSA) cycles. The QI intervention was crucial in supporting clinical staff decision making during transfers for 95% of patients who had been clinically judged as asymptomatic for COVID-19 infection. High staff engagement was observed with 83% of staff suggesting the process map was easy to follow and 92% of clinical staff agreed it contained sufficient information to support the testing process. With POCT introduction, the proportion of patients who were transferred with an early POCT result increased by 20% in the Rosewell House group and by 65% in the community Hospitals group, once governance arrangements were in place. Finally, the considerable uptake of POCT by the ward consequently led to a decrease of up to 86% in the number of samples sent to the laboratory for rapid SARS-CoV-2 testing. The quality improvement project provided a rapid and reliable SARS-CoV-2 triage tool and was effectively integrated into the geriatrics triage algorithm to facilitate patient placement and flow.
Assuntos
COVID-19 , Fragilidade , Humanos , SARS-CoV-2 , COVID-19/diagnóstico , Melhoria de Qualidade , Teste para COVID-19 , Pandemias , Testes ImediatosAssuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Biomarcadores , Eplerenona/uso terapêutico , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Prognóstico , Espironolactona/uso terapêuticoAssuntos
Galectina 3/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Espironolactona/análogos & derivados , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/fisiologia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Galectin-3 is a biomarker associated with inflammation and fibrosis that predicts adverse outcome and relates to biomarkers of extracellular matrix turnover in patients with heart failure, particularly when left ventricular (LV) systolic function is preserved. Whether galectin-3 is related to LV remodeling after acute myocardial infarction is unknown. METHODS AND RESULTS: Circulating galectin-3 and various extracellular matrix biomarkers were measured in 100 patients (age, 58.9±12.0 years; 77% men) admitted with acute myocardial infarction and LV dysfunction, at baseline (mean 46 hours) and at 24 weeks, with cardiac MRI at each time-point. LV remodeling was defined as change in LV end-systolic volume index. Relationships among galectin-3, biomarkers, and LV remodeling were analyzed across the entire cohort, then according to median baseline LV ejection fraction. Galectin-3 levels were elevated in 22 patients (22%) at baseline and increased significantly over time from 14.7±5.5 to 16.3±6.6 ng/mL (P=0.007). Baseline galectin-3 did not correlate with any LV parameters at baseline or change in any parameter over time. Galectin-3 was positively associated with remodeling in patients with supramedian baseline LV ejection fraction (ie, >49.2%; r=0.40; P=0.01) but not when LV ejection fraction was ≤49.2%. Galectin-3 correlated significantly with matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline, biomarkers that have been shown to relate to LV remodeling in this cohort. CONCLUSIONS: Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, although no definite relationship was identified with LV remodeling. Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00132093.
Assuntos
Galectina 3/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Espironolactona/análogos & derivados , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/fisiologia , Idoso , Eplerenona , Matriz Extracelular/fisiologia , Feminino , Galectina 3/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espironolactona/farmacologia , Volume Sistólico , Remodelação Ventricular/efeitos dos fármacosRESUMO
INTRODUCTION: Following acute myocardial infarction (AMI), the acute inflammatory response contributes to wound healing but also to progressive myocardial injury. Interleukin-21 (IL-21) plays a key role in immunoregulation; whether IL-21 is associated with left ventricular (LV) remodelling after AMI is unknown. METHODS: Plasma IL-21 concentrations were measured in 100 patients (age 58.9 ± 12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h) and again at 24 weeks; cardiac magnetic resonance and measurement of B-type natriuretic peptide, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-2, -3, -9, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -4 occurred at both time-points. Remodelling was defined as change in LV end-systolic volume index (ΔLVESVI). RESULTS: Plasma IL-21 concentration was unchanged over time (48.1 [SD 35.4]pg/mL at baseline vs. 48.8 [61.3]pg/mL at 24 weeks, p=0.92). Baseline IL-21 correlated significantly with ΔLVESVI (r=0.30, p=0.005) and change in LV end-diastolic volume index (r=0.33, p=0.003). On multivariate analysis, plasma IL-21 was an independent predictor of remodelling. IL-21 was also significantly associated with higher TIMP-4 concentrations and lower MMP-9 concentrations at baseline. CONCLUSIONS: IL-21 predicts adverse remodelling following AMI in patients with LV dysfunction. Whether it plays a direct pathophysiological role in remodelling merits further study.
Assuntos
Biomarcadores/sangue , Interleucinas/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Idoso , Método Duplo-Cego , Eplerenona , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Análise Multivariada , Infarto do Miocárdio/tratamento farmacológico , Valor Preditivo dos Testes , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Resultado do Tratamento , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
BACKGROUND: Alterations in the balance between matrix metalloproteinases and their endogenous tissue inhibitors (TIMPs) are associated with left ventricular (LV) remodeling after acute myocardial infarction (AMI). No relationships have been identified between TIMPs and serial postinfarction change in LV function. METHODS AND RESULTS: Plasma concentrations of TIMP-1, -2, -4 were measured at baseline (mean 46 h) and at 24 weeks in 100 patients (age 58.9 ± 12 years, 77% male) admitted with AMI and LV dysfunction, with cardiac magnetic resonance imaging at each time point. TIMP-1 concentration was reduced, whereas TIMP-2 and -4 concentrations were elevated at baseline compared with a reference control population. TIMP-1 decreased and TIMP-2 increased significantly over time; there was an incremental trend in TIMP-4 concentration. Baseline TIMP-4 correlated with change in LV end-systolic volume index (∆LVESVI; r = 0.24; P = .023) and change in LV end-diastolic volume index (∆LVEDVI; r = 0.25; P = .015). ∆TIMP-4 also correlated with ∆LVESVI and with ∆LVEDVI, as did ∆TIMP-2. On multivariable analysis, baseline TIMP-4 concentration was an independent predictor of ∆LVESVI. CONCLUSIONS: Plasma TIMP-4 concentration, measured early after AMI, may assist in the prediction of LV remodeling and therefore in the assessment of prognosis. Further study of the role of the TIMPs in the pathophysiology of postinfarction remodeling is warranted.
Assuntos
Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Inibidores Teciduais de Metaloproteinases/sangue , Remodelação Ventricular , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sístole , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/fisiopatologia , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder associated with chronic itching and skin lichenification. In lesional skin, there are apoptotic basal keratinocytes and deposits of amyloid material on degenerate keratin filaments in the upper dermis. The genetic basis of FPLCA involves mutations in the OSMR and IL31RA genes but the disease pathophysiology is not fully understood. In this study, we identified new pathogenic heterozygous missense mutations in the OSMR gene (p.Val631Leu and p.Asp647Tyr) in two Dutch FPLCA families. We then compared gene expression profiles between FPLCA lesional skin (n = 4) and site-matched control skin (n = 6). There was twofold or greater upregulation of 34 genes and downregulation of 43 genes. Most changes in gene expression (verified by quantitative RT-PCR) reflected alterations in epidermal differentiation and proliferation consistent with lichenification, but we also noted a reduction in several interfollicular keratinocyte stem cell markers in FPLCA skin. Differences in gene expression were also noted for proteins involved in apoptosis and nerve conduction. Collectively, this study expands the molecular basis of FPLCA and provides new insight into the skin pathology of this condition.
Assuntos
Amiloidose Familiar/genética , Amiloidose Familiar/metabolismo , Mutação de Sentido Incorreto/genética , Subunidade beta de Receptor de Oncostatina M/genética , Dermatopatias Metabólicas/genética , Dermatopatias Metabólicas/metabolismo , Proteínas Reguladoras de Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica , Heterozigoto , Humanos , Queratinócitos/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Países Baixos , Pele/metabolismo , Células-Tronco/metabolismo , Regulação para Cima/genéticaRESUMO
INTRODUCTION: Monocyte chemoattractant protein-1 (MCP-1) is elevated after acute myocardial infarction (AMI), and potentiates left ventricular (LV) remodeling in murine models of AMI. We examined the relationships between serum MCP-1, change in LV function and biomarkers related to remodeling in a cohort of AMI patients. METHODS: Serum MCP-1 concentrations were measured in 100 patients (age 58.9+/-12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h), 12 and 24 weeks; cardiac magnetic resonance imaging and measurement of matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9 occurred at each time-point. RESULTS: MCP-1 increased significantly from 697 [483, 997]pg/mL at baseline to 878 [678, 1130]pg/mL at 24 weeks (p<0.001). MMP-3 concentration increased while MMP-9 decreased significantly over time; MMP-2 concentration did not change significantly. BASELINE MCP-1 correlated with change in (Delta) LV end-systolic volume index (DeltaLVESVI; r= -0.48, p=0.01) and with DeltaLV ejection fraction (DeltaLVEF; r=0.50, p=0.02). However, DeltaMCP-1 correlated positively with DeltaLVESVI (r=0.40, p=0.006) and negatively with DeltaLVEF (r= -0.36, p=0.004). MCP-1 had no relationship with any MMP. CONCLUSIONS: MCP-1 may have a dichotomous role following AMI, aiding early infarct healing but potentiating later remodeling, which merits further study before any therapeutic trials of MCP-1 modulation in humans.
Assuntos
Quimiocina CCL2/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Remodelação Ventricular/fisiologia , Biomarcadores/sangue , Estudos de Coortes , Meios de Contraste , Eplerenona , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Fatores de Tempo , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Microvascular obstruction (MO) is associated with large acute myocardial infarction and lower left ventricular (LV) ejection fraction and predicts greater remodeling, but whether this effect is abolished by contemporary antiremodeling therapies is subject to debate. We examined the influence of several infarct characteristics, including MO, on LV remodeling in an optimally treated post-acute myocardial infarction cohort, using contrast-enhanced cardiac magnetic resonance. METHODS AND RESULTS: One hundred patients (mean age, 58.9+/-12 years, 77%men) underwent contrast-enhanced cardiac magnetic resonance at baseline (approximately 4 days) and at 12 and 24 weeks. The effects on LV remodeling (ie, change in LV end-systolic volume index [DeltaLVESVi]) of infarct site, transmurality, endocardial extent, and the presence of early and late MO were analyzed. Mean baseline infarct volume index decreased from 34.0 (21.2) mL/m(2) to 20.9 (12.9) mL/m(2) at 24 weeks (P<0.001). Infarct site had no influence on remodeling, but greater baseline infarct transmurality (r=0.47, P<0.001) and endocardial extent (r=0.26, P<0.01) were associated with higher DeltaLVESVi. Early MO was seen in 69 patients (69%) and persisted as late MO in 56 patients (56%). Patients with late MO underwent significantly greater remodeling than those without MO (DeltaLVESVi, +4.1 [13.4] versus -7.0 [12.7] mL/m(2), respectively, P=0.001); those with early MO only displayed an intermediate DeltaLVESVi (-4.9 [13.0] mL/m(2)). Importantly, late MO was seen frequently despite optimal coronary blood flow having been restored at angiography. CONCLUSIONS: Late MO on predischarge contrast-enhanced cardiac magnetic resonance remains an ominous predictor of adverse LV remodeling despite powerful antiremodeling therapy and may be useful in the risk stratification of survivors of acute myocardial infarction.
Assuntos
Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Distribuição de Qui-Quadrado , Meios de Contraste/administração & dosagem , Método Duplo-Cego , Eplerenona , Feminino , Gadolínio DTPA/administração & dosagem , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Angiografia por Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Infarto do Miocárdio/complicações , Placebos , Valor Preditivo dos Testes , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Estatísticas não Paramétricas , Sístole , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND: Left ventricular ejection fraction (LVEF) is a powerful prognostic marker after acute myocardial infarction and is dependent on infarct magnitude. Contrast-enhanced cardiac magnetic resonance (ceCMR) represents the current criterion standard means of LVEF and infarct size measurement. Infarct size and LVEF can be estimated from the 12-lead electrocardiogram (ECG) using the Selvester QRS score. We examined for the first time the relationship between serial measures of LVEF and infarct size by ceCMR and ECG in patients with reperfused anterior ST-elevation myocardial infarction (STEMI) and depressed LVEF. METHODS: Thirty-four patients (mean +/- SD age, 59 +/- 11.8 years; 70.6% male) underwent ceCMR and simultaneous ECG at mean 93 hours after admission and at 12 and 24 weeks. The QRS score was calculated on each ECG, from which infarct size and LVEF were estimated and compared with the equivalent ceCMR measurements. RESULTS: Infarct size on ceCMR was higher than that by QRS score at each time-point (P < .001) with modest correlation (r = 0.56-0.78, P < .001). Left ventricular ejection fraction was consistently significantly higher on CMR than on ECG, with weak correlation (r = 0.37-0.51, P < .05). We derived a novel equation relating QRS score to CMR-measured LVEF in the subacute phase of infarction: LVEF = 61 - (1.7 x QRS score) (%). CONCLUSIONS: In patients with reperfused anterior ST-elevation myocardial infarction and depressed LVEF, ceCMR is moderately correlated with the QRS in the serial measurement of infarct size and LVEF. Infarct size (measured by ceCMR) and LVEF are consistently higher than those calculated on the QRS score in the acute and subacute phases of infarction.
Assuntos
Eletrocardiografia/métodos , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/terapia , Reperfusão Miocárdica , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/prevenção & controle , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologiaRESUMO
OBJECTIVES: This study sought to assess, for the first time, the relationship between serum concentrations of the soluble interleukin-1 receptor family member ST2 (sST2) and serial change in left ventricular (LV) function after acute myocardial infarction (AMI). BACKGROUND: Serum sST2 levels are elevated early after AMI and are associated with lower pre-discharge LV ejection fraction and adverse cardiovascular outcomes. METHODS: The sST2 levels were measured in 100 patients (mean age 58.9 +/- 12.0 years; 77% male), admitted with AMI with resultant LV systolic dysfunction, at baseline and at 12 and 24 weeks. Patients underwent cardiac magnetic resonance imaging and measurement of N-terminal pro-brain natriuretic peptide, norepinephrine, and aldosterone at each time point. RESULTS: Median sST2 decreased from 263.3 pg/ml at baseline to 140.0 pg/ml at 24 weeks (p < 0.001). Serum sST2 correlated significantly with LV ejection fraction at baseline (r = -0.30, p = 0.002) and 24 weeks (r = -0.23, p = 0.026); change in sST2 correlated with change in LV end-diastolic volume index (r = -0.24, p = 0.023). Level of sST2 was positively associated with infarct volume index at baseline (r = 0.26, p = 0.005) and 24 weeks (r = 0.22, p = 0.037), and with change in infarct volume index (r = -0.28, p = 0.001). Level of sST2 was significantly higher in patients with greater infarct transmurality and endocardial extent, and in the presence of microvascular obstruction. Level of sST2 correlated significantly with norepinephrine and aldosterone, but not with N-terminal pro-brain natriuretic peptide. CONCLUSIONS: Measurement of sST2 early after AMI assists in the prediction of medium-term LV functional recovery. Novel relationships were observed between sST2, infarct magnitude/evolution, and aldosterone. Serum sST2 may be of pathophysiological importance in ventricular and infarct remodeling after AMI. (Effects of Eplerenone on Left Ventricular Remodelling Following Heart Attack; NCT00132093).
Assuntos
Infarto do Miocárdio/sangue , Receptores de Superfície Celular/sangue , Volume Sistólico/fisiologia , Remodelação Ventricular/fisiologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Método Duplo-Cego , Eplerenona , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Valor Preditivo dos Testes , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Remodelação Ventricular/efeitos dos fármacosRESUMO
Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as beta1 and alpha6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kindler syndrome.
Assuntos
Anormalidades Múltiplas/genética , Integrinas/metabolismo , Proteínas de Membrana/genética , Mutação/genética , Proteínas de Neoplasias/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Membrana Basal/metabolismo , Membrana Basal/patologia , Adesão Celular , Membrana Celular/metabolismo , Criança , Pré-Escolar , Epiderme/metabolismo , Epiderme/patologia , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Queratina-15/genética , Queratina-15/metabolismo , Queratinócitos/patologia , Masculino , Proteínas de Membrana/metabolismo , Microscopia de Fluorescência , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fenótipo , SíndromeRESUMO
Hereditary conditions are traditionally classified based either on physical/physiological attributes or using the names of the individuals credited with identifying the condition. For the 170 plus conditions classified as ectodermal dysplasias (EDs), both of these nosological systems are used, at times interchangeably. Over the past decade our knowledge of the human genome and the molecular basis of the EDs have greatly expanded providing the impetus to consider alternative classification systems. The incorporation of the molecular basis of hereditary conditions adds important information allowing effective transfer of objective genetic information that can be lacking from traditional classification systems. Molecular information can be added to the nosological system for the EDs through a hierarchical- and domain-based approach that encompasses the condition's name, mode of inheritance, molecular pathway affected, and specific molecular change. As new molecular information becomes available it can be effectively incorporated using this classification approach. Integrating molecular information into the ED classification system, while retaining well-recognized traditional syndrome names, facilitates communication at and between different groups of people including patients, families, health care providers, and researchers.
Assuntos
Displasia Ectodérmica/classificação , Displasia Ectodérmica/genética , Predisposição Genética para Doença , Biologia Molecular , Proteínas , Displasia Ectodérmica/fisiopatologia , Ectodisplasinas/genética , Genótipo , Humanos , Queratinas/genética , Biologia Molecular/métodos , Mutação , Proteínas/genética , Proteínas/metabolismo , Transativadores/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/genéticaAssuntos
Desenvolvimento Embrionário/fisiologia , Hipoplasia Dérmica Focal , Proteínas de Membrana/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Aciltransferases , Desenvolvimento Embrionário/genética , Hipoplasia Dérmica Focal/genética , Hipoplasia Dérmica Focal/patologia , Humanos , Proteínas de Membrana/genética , Fenótipo , Proteínas Wnt/genéticaRESUMO
AIMS: Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and heart failure or diabetes after acute myocardial infarction (AMI). The mechanism of this effect is unclear. We performed a contrast-enhanced cardiac magnetic resonance study to assess the effects of eplerenone on LV remodeling after AMI. METHODS: One hundred patients (mean age, 58.9 +/- 12 years; 77% male) with LV systolic dysfunction but without heart failure or diabetes were randomized to 24 weeks' double-blind treatment with eplerenone or placebo started 1 to 14 days after AMI. Contrast-enhanced cardiac magnetic resonance was performed, and plasma concentrations of matrix metalloproteinase-2 (MMP-2) and MMP-9 were measured before randomization and at 12 and 24 weeks. RESULTS: Baseline LV ejection fraction was, by chance, significantly higher in eplerenone than in placebo-treated patients. Eplerenone had no effect on the primary end point (change in LV end-systolic volume index); after covariate adjustment, the primary end point fell by 6.1 +/- 2.7 mL/m2 with eplerenone compared to placebo (P = .027), and LV end-diastolic volume index fell by 7.5 +/- 3.4 mL/m2 (P = .031); eplerenone did not significantly influence LV ejection fraction. Eplerenone, after covariate adjustment, significantly decreased MMP-2 and increased MMP-9 over 24 weeks relative to placebo. CONCLUSIONS: In a population of patients with AMI with high uptake of contemporary antiremodeling therapy, eplerenone provides modest incremental protection against LV remodeling, only after covariate adjustment.
Assuntos
Antagonistas de Receptores de Mineralocorticoides/farmacologia , Infarto do Miocárdio/fisiopatologia , Espironolactona/análogos & derivados , Remodelação Ventricular/efeitos dos fármacos , Idoso , Biomarcadores/sangue , Método Duplo-Cego , Eplerenona , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Espironolactona/farmacologia , Resultado do TratamentoRESUMO
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.
Assuntos
Fenda Labial , Fissura Palatina , Displasia Ectodérmica , Pálpebras/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Animais , Criança , Pré-Escolar , Fenda Labial/diagnóstico , Fenda Labial/genética , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Humanos , Lactente , Recém-Nascido , Mutação , Síndrome , Transativadores/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVES: All patients should undergo formal assessment of ventricular function following acute myocardial infarction (AMI). Cardiac magnetic resonance (CMR) is not widely used as a test before discharge in AMI patients. This study sought to determine the impact of contrast-enhanced CMR (ceCMR) scanning before discharge in addition to standard transthoracic echocardiography (TTE) on patient care following AMI. METHODS: 100 patients admitted with AMI, all of whom had a left ventricular ejection fraction (LVEF) <40% on TTE, underwent ceCMR imaging before discharge. Abnormalities of clinical relevance detected on ceCMR, which influenced patient management, are reported. RESULTS: Each patient (77% male, mean age 58.9 years, SD 12) underwent TTE and ceCMR at a mean 1.4 (range 0.8-3.2) and 4.2 days (range 2-11), respectively, following admission. ceCMR significantly influenced the management of 24/100 (24%) of the patient cohort, through detection of LV thrombus, right ventricular infarction, intracardiac neoplasia, and a variety of intrathoracic and intra-abdominal pathology. There were no issues regarding safety in this high-risk group of patients. CONCLUSION: In a cohort of AMI patients with reduced LVEF, ceCMR scanning before discharge improved the management of 24% of the cohort. ceCMR is a useful and safe adjunct to standard care after AMI.
Assuntos
Imageamento por Ressonância Magnética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Disfunção Ventricular Esquerda/patologia , Idoso , Estudos de Coortes , Ecocardiografia , Feminino , Átrios do Coração , Neoplasias Cardíacas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mixoma/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose/diagnósticoRESUMO
Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome. These mutations give rise to mutant p63alpha protein isoforms with dominant effects towards their wild-type counterparts. Here we report four RHS/AEC-like patients with mutations (p.Gln9fsX23, p.Gln11X, p.Gln16X), that introduce premature termination codons in the N-terminal part of the p63 protein. These mutations appear to be incompatible with the current paradigms of dominant-negative/gain-of-function outcomes for other p63 mutations. Moreover it is difficult to envisage how the remaining small N-terminal polypeptide contributes to a dominant disease mechanism. Primary keratinocytes from a patient containing the p.Gln11X mutation revealed a normal and aberrant p63-related protein that was just slightly smaller than the wild-type p63. We show that the smaller p63 protein is produced by translation re-initiation at the next downstream methionine, causing truncation of a non-canonical transactivation domain in the DeltaN-specific isoforms. Interestingly, this new DeltaDeltaNp63 isoform is also present in the wild-type keratinocytes albeit in small amounts compared with the p.Gln11X patient. These data establish that the p.Gln11X-mutation does not represent a null-allele leading to haploinsufficiency, but instead gives rise to a truncated DeltaNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the DeltaNp63alpha isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.