RESUMEN
Late arterial hypertension has been identified as a major predictor for morbidity and mortality in aortic coarctation (AoC) patients. Few data are available about efficacy and tolerability of angiotensin converting enzyme inhibitors vs beta-blockers in young AoC patients. This study aimed to evaluate the tolerability and efficacy on 24-h blood pressure (BP) and left ventricular mass/height(2.7) (LVMI), of atenolol vs enalapril. We enrolled consecutive AoC hypertensive patients with (a) no history of BP treatment or after >48 h of withdrawn, (b) aged 6-20 years, (c) body mass index (BMI) <90th percentile for age and sex, (d) >12 months from a successful AoC repair and (e) no major associated cardiovascular abnormalities. All patient were evaluated with 24-h ambulatory BP monitoring, standard echocardiography, strain-strain rate imaging, at enrolment, 3, 6 and 12 months of treatment. We studied 51 AoC patients (13±3.9 years, BMI: 21.4±4.3 kg m(-2)). Patients were randomly assigned at atenolol treatment (n=26), or enalapril treatment (n=25). The mean follow-up duration was 11±2 months. Both drugs were able to significantly reduce 24-systolic BP (SBP; atenolol: 133±11 mm Hg vs 124±16 mm Hg, P=0.016; enalapril: 135±6 mm Hg vs 127±7 mm Hg, P=0.001). Only enalapril was able to significantly reduce LVMI (47±12 vs 39.6±10 g m(-)(2.7), P=0.016). Only in atenolol group in two cases (7.7%) drug withdrawal was needed because of adverse events. Enalapril and atenolol are similarly effective in reducing SBP. However, only enalapril demonstrated a significant reduction of LVMI. In no case, enalapril was stopped because of adverse events.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Coartación Aórtica/cirugía , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Procedimientos Quirúrgicos Cardíacos , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/efectos adversos , Coartación Aórtica/complicaciones , Coartación Aórtica/diagnóstico , Coartación Aórtica/fisiopatología , Atenolol/efectos adversos , Niño , Enalapril/efectos adversos , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/etiología , Hipertensión/fisiopatología , Italia , Masculino , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To confirm rates of infections from a previous survey in chronic hemodialysis patients; to get information about incidents and manipulations of vascular access-site, number and reasons of hospitalisation; to asses a relationship between the frequency of vascular access-site infections (VASI) and quality of care during the procedures of vascular access-site use. DESIGN: Prospective, multicenter survey performed from February 2000 to January 2001, including all patients underwent chronic hemodialysis in 5 participating centers. Standardized definitions used and different clinical and biological risk factors recorded. RESULTS: 429 patients for a total of 4273 dialysis months (DM) were enrolled. 245 infections in 164 infected patients were reported. The overall rate was 5.73 infections per 100 DM (18 VASI, 25 bacteraemia, 84 respiratory, 29 urinary tract, 1 endocarditis and 88 other infections). 50% of infections were microbiologically documented. 19 of 21 antibiotics resistant microorganisms were meticillin resistant Staphylococcus aureus. Compared to the incidence rate of fistula (0.05 per 1000 days of follow-up) or prosthesis related VASI (0.11), the incidence rate of catheter related VASI (0.65) was significantly higher. Poor hygiene and duration of catheter use were the significant risk factors for VASI showed by logistic analysis regression. VASI and bacteraemia occurred more frequently after incident or manipulation of the vascular access-site. The decrease of VASI between the 2 periods of survey was significantly higher in centers having reduced the catheter use and implemented written protocols. CONCLUSIONS: This second period of surveillance has confirmed the frequency of infections rate in chronic hemodialysis patients and particularly bacteraemia and VASI. This study has allowed to establish risk factors for infections and showed that VASI in hemodialysis are related to factors in part preventable.
Asunto(s)
Infecciones/epidemiología , Diálisis Renal/efectos adversos , Anciano , Nefropatías Diabéticas , Femenino , Francia , Humanos , Incidencia , Infecciones/clasificación , Masculino , Factores de Riesgo , Factores de TiempoRESUMEN
TIE1, an endothelial-cell-specific tyrosine kinase receptor, is required for the survival and growth of microvascular endothelial cells during the capillary sprouting phase of vascular development. To investigate the molecular mechanisms that regulate the expression of TIE1 in the endothelium, we analysed transgenic mouse embryos carrying wild-type or mutant TIE1 promoter/LacZ constructs. Our data indicate that an upstream DNA octamer element (5'-ATGCAAAT-3') is required for the in vivo expression of TIE1 in embryonic endothelial cells. Transgenic embryos carrying the wild-type TIE1 promoter (-466 to +78 bp) fused to LacZ and spanning the octamer element demonstrate endothelial-cell-specific expression of the reporter transgene. Point mutations introduced within the octamer element result in a significant decrease of endothelial LacZ expression, suggesting that the octamer site functions as a positive regulator for TIE1 gene expression in endothelial cells. DNA-protein binding studies show that the octamer element exhibits an endothelial-cell-specific pattern of binding via interaction with endothelial-cell-restricted factor(s). Our findings suggest an important role for the octamer element in regulating the expression of the TIE1 receptor in the embryonic endothelium and suggest a common mechanism for the regulation of the angiogenic and cell-specific TIE1 and TIE2 genes during vascular development.
Asunto(s)
Endotelio/metabolismo , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Proteínas Tirosina Quinasas Receptoras/química , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/química , Animales , Células Cultivadas , ADN/metabolismo , Endotelio/citología , Genotipo , Ratones , Ratones Transgénicos , Mutación , Mutación Puntual , Receptor TIE-1 , Receptores TIE , Transcripción Genética , Transfección , Transgenes , beta-Galactosidasa/metabolismoRESUMEN
Endothelin-1 (ET-1) plays an important role in the development, physiology and pathophysiology of the cardiovascular system in mammals. ET-1 is mainly expressed in endothelial cells thus making it an attractive model for the study of transcriptional regulation in this cell type. We have previously reported that expression of the human ET-1 gene is positively regulated by a cooperative interaction between GATA-2 and AP-1 transcription factors in cultured endothelial cells, however these factors are not sufficient to mediate cell type-specific expression. In vivo transcription studies of the murine ET-1 gene have demonstrated the presence of important cell-specific DNA elements in the 5.9 kb region upstream of the transcription initiation site. Using reporter gene transfection, site-directed mutagenesis and DNA-protein binding studies of the 5.9 kb region, we have identified a tripartite DNA element that positively regulates the expression of ET-1 specifically in cultured endothelial cells. This complex enhancer element demonstrates an endothelial cell-specific pattern of binding, suggesting that it interacts with cell-restricted regulatory factors. These findings provide important insights into the mechanisms that mediate the expression of ET-1 in the endothelium and a basis for future transgenic and cloning studies aimed at identifying the endothelial cell-specific binding site and transcription factor(s).
Asunto(s)
Endotelina-1/genética , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Células 3T3 , Animales , Células Cultivadas , Endotelio Vascular/citología , Glioma , Humanos , Ratones , Ratones Transgénicos , Secuencias Reguladoras de Ácidos Nucleicos , Transcripción Genética , TransfecciónRESUMEN
The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiac performance are detected with small variations in thyroid hormone serum concentrations. Most patients with hyperthyroidism experience cardiovascular manifestations, and the most serious complications of hyperthyroidism occur as a result of cardiac involvement. Recent studies provide important insights into the molecular pathways that mediate the action of thyroid hormone on the heart and allow a better understanding of the mechanisms that underlie the hemodynamic and clinical manifestations of hyperthyroidism. Several cardiovascular conditions and drugs can interfere with thyroid hormone levels and may pose a difficulty in interpretation of laboratory data in patients with suspected thyroid heart disease. The focus of this report is a review of the current knowledge of thyroid hormone action on the heart and the clinical and hemodynamic laboratory findings as well as therapeutic management of patients with hyperthyroid heart disease.
Asunto(s)
Cardiopatías/fisiopatología , Corazón/fisiología , Hipertiroidismo/fisiopatología , Hormonas Tiroideas/fisiología , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Corazón/fisiopatología , Cardiopatías/etiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertiroidismo/complicaciones , Contracción Miocárdica , Miocardio/citología , Tiroxina/fisiología , Triyodotironina/fisiologíaRESUMEN
The TIE2 gene, also known as TEK, encodes a tyrosine kinase receptor that is required for the normal development of the vascular system during embryogenesis. TIE2 is specifically expressed in endothelial cells; however, the transcriptional mechanisms that regulate this highly restricted pattern of expression remain unknown. Here we demonstrate that a consensus octamer element located in the 5'-flanking region of TIE2 is required for normal expression in embryonic endothelial cells. Transgenic embryos carrying a TIE2/LacZ construct spanning 2.1 kilobases of upstream regulatory sequences exhibit expression of the reporter transgene specifically in endothelial cells. Site-directed mutagenesis of a consensus octamer element located in this region results in the loss of enhancer activity and significantly impairs the endothelial expression of the reporter transgene. Consistent with the in vivo data, in vitro DNA-protein binding studies show that the consensus octamer element displays an endothelial cell-specific pattern of binding, suggesting an interaction with a protein complex consisting of Oct1 and an endothelial cell-restricted cofactor. These data identify a novel role for the octamer element as an essential regulator of TIE2 expression, define the first known transcriptional pathway that mediates the expression of a developmental endothelial cell gene, and provide insights into the transcriptional mechanisms that regulate development of the vasculature during embryogenesis.
Asunto(s)
Endotelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Secuencia de Bases , Biopolímeros , ADN , Proteínas de Unión al ADN/metabolismo , Endotelio/citología , Elementos de Facilitación Genéticos , Factor C1 de la Célula Huésped , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Factor 1 de Transcripción de Unión a Octámeros , Receptor TIE-2 , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/metabolismoRESUMEN
CONTEXT: Which drug is most effective as a first-line treatment for stable angina is not known. OBJECTIVE: To compare the relative efficacy and tolerability of treatment with beta-blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina. DATA SOURCES: We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies. STUDY SELECTION: Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (beta-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria. DATA EXTRACTION: Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine). DATA SYNTHESIS: Rates of cardiac death and myocardial infarction were not significantly different for treatment with beta-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05) fewer episodes of angina per week with beta-blockers than with calcium antagonists. beta-Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between beta-blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with beta-blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or beta-blockers to draw firm conclusions about relative efficacy. CONCLUSIONS: beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Angina de Pecho/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Nitratos/uso terapéutico , Ensayos Clínicos como Asunto , HumanosAsunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Angina de Pecho/terapia , Bloqueadores de los Canales de Calcio/uso terapéutico , Terapias Complementarias/métodos , Nitratos/uso terapéutico , Medicina Basada en la Evidencia , Humanos , Nifedipino/uso terapéutico , Nitroglicerina/uso terapéutico , Resultado del Tratamiento , Vasodilatadores/uso terapéuticoRESUMEN
To investigate the molecular basis of endothelial cell-specific gene expression, we have examined the DNA sequences and the cognate DNA-binding proteins that mediate transcription of the murine tie2/tek gene. Reporter transfection experiments conformed with earlier findings in transgenic mice, indicating that the upstream promoter of Tie2/Tek is capable of activating transcription in an endothelial cell-specific fashion. These experiments have also allowed the identification of a single upstream inhibitory region (region I) and two positive regulatory regions (regions U and A) in the proximal promoter. Electrophoretic mobility-shift assays have allowed further characterization of three novel DNA-binding sequences associated with these regions and have provided preliminary characterization of the protein factors binding to these elements. Two of the elements (U and A) confer increased transcription on a heterologous promoter, with element U functioning in an endothelial-cell-selective manner. By employing embryonic endothelial-like yolk sac cells in parallel with adult-derived endothelial cells, we have identified differences in functional activity and protein binding that may reflect mechanisms for specifying developmental regulation of tie2/tek expression. Further study of the DNA and protein elements characterized in these experiments is likely to provide new insight into the molecular basis of developmental- and cell-specific gene expression in the endothelium.
Asunto(s)
Endotelio Vascular/fisiología , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Secuencia de Bases , Bovinos , Huella de ADN , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Ratas , Receptor TIE-2 , Mapeo Restrictivo , Transcripción Genética , TransfecciónRESUMEN
We have isolated overlapping cDNAs encoding the N-terminal non-triple-helical region of mouse alpha 1(XVIII) collagen and shown that three different variants of alpha 1(XVIII) collagen exist. Each of the three variants shows characteristic tissue-specific expression patterns. Immunohistochemical studies show positive staining for alpha 1(XVIII) collagen along the basement membrane zones of vessels in the intestinal villi, the choroid plexus, skin, liver, and kidney. Thus, we conclude that alpha 1(XVIII) collagen may interact (directly or indirectly) with components in basement membrane zones or on the basal surface of endothelial/epithelial cells.