RESUMEN

PURPOSE: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. DESIGN: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. RESULTS: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TßRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. CONCLUSIONS: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bevacizumab , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Everolimus , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neuropilina-1/genética , Neuropilina-1/metabolismo , Neuropilina-2/genética , Neuropilina-2/metabolismo , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

BACKGROUND: Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology development. Our goal was to describe the cardiovascular clinical research portfolio from ClinicalTrials.gov. METHODS AND RESULTS: We identified 40 970 clinical research studies registered between 2007 and 2010 in which patients received diagnostic, therapeutic, or other interventions per protocol. By annotating 18 491 descriptors from the National Library of Medicine's Medical Subject Heading thesaurus and 1220 free-text terms to select those relevant to cardiovascular disease, we identified studies that related to the diagnosis, treatment, or prevention of diseases of the heart and peripheral arteries in adults (n = 2325 [66%] included from review of 3503 potential studies). The study intervention involved a drug in 44.6%, a device or procedure in 39.3%, behavioral intervention in 8.1%, and biological or genetic interventions in 3.0% of the trials. More than half of the trials were postmarket approval (phase 4, 25.6%) or not part of drug development (no phase, 34.5%). Nearly half of all studies (46.3%) anticipated enrolling 100 patients or fewer. The majority of studies assessed biomarkers or surrogate outcomes, with just 31.8% reporting a clinical event as a primary outcome. CONCLUSIONS: Cardiovascular studies registered on ClinicalTrials.gov span a range of study designs. Data have limited verification or standardization and require manual processes to describe and categorize studies. The preponderance of small and late-phase studies raises questions regarding the strength of evidence likely to be generated by the current portfolio and the potential efficiency to be gained by more research consolidation.

Asunto(s)

Investigación Biomédica , Enfermedades Cardiovasculares , Ensayos Clínicos como Asunto , Sistema de Registros , Humanos , Internet

RESUMEN

AIMS: Beta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction. However, there is heterogeneity in the response to these drugs, perhaps due to genetic variations in the ß1-adrenergic receptor (ADRß1). We examined whether the Arg389Gly polymorphism in ADRß1 interacts with the dose requirements of beta-blockers in patients with systolic HF. METHODS AND RESULTS: HF-ACTION was a randomized, multicentre trial of ambulatory HF patients with systolic dysfunction who were randomized to exercise training or usual care. A subset of patients provided DNA. The relationships among beta-blocker dose, ADRß1-389 genotype, and outcomes were assessed using the Cox proportional hazards regression model. The interaction between beta-blocker dose and the ADRß1-389 genotype was tested. DNA information was available for 957 patients. The alleles did not deviate from Hardy-Weinberg equilibrium. Patients with the ADRß1-389 Arg/Arg genotype receiving low-dose beta-blockers had a two-fold increase in the risk of death compared with those receiving a high dose (hazard ratio 2.09; P = 0.015); this was not conferred in Gly carriers. There was also an interaction between improvements in Kansas City Cardiomyopathy Questionnaire score and beta-blocker dose by genotype, suggesting that higher doses of beta-blockade might be needed to achieve benefit in Arg/Arg genotype patients. CONCLUSION: There was a gene-dose interaction with the ADRß1-389 Arg/Arg vs. Gly carrier genotype and beta-blocker dose, suggesting that patients with the Arg/Arg genotype might require a higher dose of beta-blockade to achieve a treatment response similar to that of Gly carriers.

Asunto(s)

Antagonistas Adrenérgicos beta/uso terapéutico , Resistencia a Medicamentos/genética , Insuficiencia Cardíaca/genética , Receptores Adrenérgicos beta 1/genética , Anciano , Estudios de Cohortes , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Resultado del Tratamiento

RESUMEN

Unlike traditional small molecule (chemical) drug products, the development of biologic products is very different and variable with respect to the manufacturing process and environmental factors such as light and temperature. The complexity and heterogeneity of the molecular structure, complicated manufacturing process, different analytical methods, and possibility of severe immunogenicity reactions make quantitative evaluation of follow-on biologics a great challenge to both scientific community and regulatory agencies. In this article, we propose a general approach for development of a biosimilarity index based on the concept of reproducibility probability for quantitative evaluation of biosimilarity and interchangeability. The proposed method is robust regardless the biosimilarity criteria used and/or study design employed.

Asunto(s)

Algoritmos , Biosimilares Farmacéuticos , Sustitución de Medicamentos/estadística & datos numéricos , Estudios Cruzados , Humanos , Estados Unidos

RESUMEN

OBJECTIVES: The aim of this study was to evaluate the independent prognostic significance of ischemia change in stable coronary artery disease (CAD). BACKGROUND: Recent randomized trials in stable CAD have suggested that revascularization does not improve outcomes compared with optimal medical therapy (MT). In contrast, the nuclear substudy of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial found that revascularization led to greater ischemia reduction and suggested that this may be associated with improved unadjusted outcomes. Thus, the effects of MT versus revascularization on ischemia change and its independent prognostic significance requires further investigation. METHODS: From the Duke Cardiovascular Disease and Nuclear Cardiology Databanks, 1,425 consecutive patients with angiographically documented CAD who underwent 2 serial myocardial perfusion single-photon emission computed tomography scans were identified. Ischemia change was calculated for patients undergoing MT alone, percutaneous coronary intervention, or coronary artery bypass grafting. Patients were followed for a median of 5.8 years after the second myocardial perfusion scan. Cox proportional hazards regression modeling was used to identify factors independently associated with the primary outcome of death or myocardial infarction (MI). Formal risk reclassification analyses were conducted to assess whether the addition of ischemia change to traditional predictors resulted in improved risk classification for death or MI. RESULTS: More MT patients (15.6%) developed ≥5% ischemia worsening compared with those undergoing percutaneous coronary intervention (6.2%) or coronary artery bypass grafting (6.7%) (p < 0.001). After adjustment for established predictors, ≥5% ischemia worsening remained a significant independent predictor of death or MI (hazard ratio: 1.634; p = 0.0019) irrespective of treatment arm. Inclusion of ≥5% ischemia worsening in this model resulted in significant improvement in risk classification (net reclassification improvement: 4.6%, p = 0.0056) and model discrimination (integrated discrimination improvement: 0.0062, p = 0.0057). CONCLUSIONS: In stable CAD, ischemia worsening is an independent predictor of death or MI, resulting in significantly improved risk reclassification when added to previously known predictors.

Asunto(s)

Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Infarto del Miocardio/etiología , Infarto del Miocardio/mortalidad , Isquemia Miocárdica/etiología , Isquemia Miocárdica/mortalidad , Anciano , Fármacos Cardiovasculares/efectos adversos , Distribución de Chi-Cuadrado , Angiografía Coronaria , Puente de Arteria Coronaria/efectos adversos , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/terapia , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/terapia , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/terapia , Imagen de Perfusión Miocárdica/métodos , North Carolina , Intervención Coronaria Percutánea/efectos adversos , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento

RESUMEN

BACKGROUND: Understanding past trends and predicted future incidence of hip fractures is important for the assessment of Medicare sustainability and resource allocation. The purpose of this article was an analysis of most recent data on the incidence of hip fractures to predict the number of hip fractures that will occur in the United States from 2010 to 2050 in individuals 45 and older, by sex, and age distribution. METHOD: Prior hip fracture data were obtained from the National Hospital Discharge Survey during the period 1996-2006. These data were obtained from the US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Projected population estimates were obtained from the Population Division, US Census Bureau and Statistics, August 14, 2008. We used the past number and incidence of hip fractures extrapolated to population projections to predict the future number of hip fractures to 2050 using Application Software (SAS 9.2; SAS Institute Inc) regression model analysis. RESULTS: Two trends were identified from past reported rates of hip fractures. Trend 1 assumed a continued very slow decline in the incidence of hip fractures in the future yielding a conservative estimate of 458,000 fractures by 2050. Trend 2 ignored the slight decrease in rate over past years and used a constant rate determined from linear regression providing an estimate as high as 1,037,000 in 2050. The largest number of fractures will occur in females older than 65 years. CONCLUSIONS: Future estimates of the number of hip fracture will likely fall between the 2 trends described within and by 2050 may range from 458,000 to 1,037,000 with the largest number occurring in female older than 65 years.

Asunto(s)

Predicción , Fracturas de Cadera/epidemiología , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Medición de Riesgo , Estados Unidos/epidemiología , Adulto Joven

RESUMEN

BACKGROUND: This post hoc analysis of the HF-ACTION cohort explores the primary and secondary results of the HF-ACTION study by etiology and severity of illness. METHODS: HF-ACTION randomized stable outpatients with reduced left ventricular (LV) function and heart failure (HF) symptoms to either supervised exercise training plus usual care or to usual care alone. The primary outcome was all-cause mortality or all-cause hospitalization; secondary outcomes included all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization. The interaction between treatment and risk variable, etiology or severity as determined by risk score, New York Heart Association class, and duration of cardiopulmonary exercise test was examined in a Cox proportional hazards model for all clinical end points. RESULTS: There was no interaction between etiology and treatment for the primary outcome (P = .73), cardiovascular (CV) mortality or CV hospitalization (P = .59), or CV mortality or HF hospitalization (P = .07). There was a significant interaction between etiology and treatment for the outcome of mortality (P = .03), but the interaction was no longer significant when adjusted for HF-ACTION adjustment model predictors (P = .08). There was no significant interaction between treatment effect and severity, except a significant interaction between cardiopulmonary exercise duration and training was identified for the primary outcome of all-cause mortality or all-cause hospitalization. CONCLUSION: Consideration of symptomatic (New York Heart Association classes II to IV) patients with HF with reduced LV function for participation in an exercise training program should be made independent of the cause of HF or the severity of the symptoms.

Asunto(s)

Terapia por Ejercicio , Insuficiencia Cardíaca Sistólica/terapia , Anciano , Femenino , Insuficiencia Cardíaca Sistólica/etiología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Disfunción Ventricular Izquierda

RESUMEN

BACKGROUND: Vitamin D is implicated in various biological functions ranging from cellular proliferation to immunity. Vitamin D deficiency is associated with an increased risk of several diseases including coronary atherosclerosis. MATERIALS AND METHODS: We measured plasma 25(OH)D3 level in 224 patients with acute coronary syndromes (ACS) and 209 control individuals by ELISA. We genotyped the study populations for 11 single nucleotide polymorphisms (SNPs) in seven genes involved in vitamin D biosynthesis and metabolism by 5' nuclease assays. RESULTS: The mean and median plasma 25(OH)D3 levels were not significantly different between patients with ACS and controls (median: 22·06 vs. 22·24 ng mL(-1) , respectively, P = 0·618). Plasma 25(OH)D3 level was < 20 ng mL(-1) in 175/433 (40%) and < 30 ng mL(-1) in 333/433 (77%) participants. Only four individuals had plasma 25(OH)D3 levels of above 60 ng mL(-1) . African-American and Hispanic populations, women and those with diabetes mellitus had significantly lower plasma 25(OH)D3 levels. In multivariable regression analysis, age, sex, diabetes mellitus, body weight, rs2762933 (CYP24A1) and rs6055987 (PLCB1) SNPs were independent predictors of plasma 25(OH)D3 level in the Caucasian population. CONCLUSIONS: We found no difference in mean plasma vitamin D levels between patients with ACS and controls. Differences in population characteristics between the two study groups including medications use and the lack of data on vitamin D, calcium and multivitamin supplements intake as well as the relatively small sample size of the populations could confound the results. Ethnic background, sex, age, body weight and SNPs in CYP24A1 and PLCB1 were independent determinants of plasma vitamin D levels.

Asunto(s)

Síndrome Coronario Agudo/sangre , Deficiencia de Vitamina D/sangre , Vitamina D/sangre , Síndrome Coronario Agudo/genética , Adulto , Anciano , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Regresión , Deficiencia de Vitamina D/genética

RESUMEN

BACKGROUND: The association of sustained ventricular tachycardia/fibrillation (VT/VF) with mortality in patients undergoing primary percutaneous coronary intervention (PCI) may vary with baseline patient risk and may be associated with higher mortality in patients who have high-risk baseline features but not in the low-risk patient cohort undergoing this procedure. METHODS: Among the 5,259 ST Elevation Myocardial Infarction (STEMI) patients presenting for primary PCI from the APEX AMI trial, we evaluated the association of VT/VF with outcomes according to underlying risk for 90-day mortality estimated using baseline variables and with a Cox regression model. RESULTS: Ventricular tachycardia/fibrillation occurred in 3.6% (63/1,736), 4.9% (87/1,788), and 8.1% (141/1,735) of patients in the low-, intermediate-, and high-tertiles of 90-day predicted death, respectively. Ninety-day death was between 3.2- and 4.8-fold higher in patients with VT/VF compared with those without it in the 3 risk groups (low risk 1.6% vs 0.5%, intermediate risk 5.7% vs 1.2%, high risk 33.6% vs 7.7%). Both early (during cardiac catheterization) and late VT/VF (after cardiac catheterization) were associated with high risk of death regardless of baseline risk category. CONCLUSIONS: The incidence of VT/VF and mortality increased as patients' baseline risk increased, and VT/VF remained an important prognostic marker for the increased risk of clinical adverse events and 90-day mortality irrespective of underlying baseline risk in patients undergoing primary PCI. Thus, even in otherwise low-risk patients, occurrence of VT/VF helps to further identify higher risk cohort that may warrant closer monitoring.

Asunto(s)

Angioplastia Coronaria con Balón/efectos adversos , Taquicardia Ventricular/mortalidad , Fibrilación Ventricular/mortalidad , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo

RESUMEN

UNLABELLED: Atherosclerosis develops in an environment of endothelial injury and inflammation. Circulating endothelial progenitor cells (EPCs) are required for vascular repair and restoration of normal endothelial function. We tested the hypothesis that the nonselective cyclooxygenase (COX) inhibitor aspirin (ASA) exerts an effect on circulating EPCs. METHODS: As part of a larger study evaluating the effect of aspirin dose in primary and secondary prevention, subjects (n=32) were assigned randomly to either 81 mg or 325 mg aspirin daily for two months, and circulating mononuclear cells were enumerated at the beginning of the study and after 2 months using fluorescent antibodies against CD34 and CD133 as well as based on aldehyde dehydrogenase (ALDH) activity. Brachial artery endothelial function via flow-mediated dilation (BAFMD) and light transmittance platelet aggregometry in response to physiologic agonists was also determined. RESULTS: Subjects taking aspirin at the time of study entry had a lower numbers of CD133+/34+ cells compared to those not previously exposed (0.01% vs. 0.05% of MNCs, P<0.03). After 2 months, subjects randomized to 81 vs. 325 mg of ASA had no significant differences in the median numbers of EPCs, although mean numbers trended lower in the high dose group. Patients on chronic ASA therapy continued to have lower numbers of EPCs. Similar effects were observed in CD34 and CD 133 single-positive cells, as well as ALDH(br) cells. BAFMD did not differ nor change significantly over time between aspirin dose groups. All patients had decreased ex vivo platelet aggregation in response to arachidonic acid and ADP stimulation. CONCLUSIONS: Our preliminary studies suggest that aspirin exerts a time-dependent effect on circulating EPCs. Short-term exposure to differing doses of ASA had indeterminate effects on EPCs levels, suggesting that time of ASA exposure may play a more important role than dose. Determining the responsible mechanism(s) and the overall clinical relevance of these findings will require further investigation.

Asunto(s)

Aspirina/administración & dosificación , Inhibidores de la Ciclooxigenasa/administración & dosificación , Células Endoteliales/efectos de los fármacos , Células Madre/efectos de los fármacos , Antígeno AC133 , Adulto , Anciano , Anciano de 80 o más Años , Aldehído Deshidrogenasa/metabolismo , Antígenos CD/análisis , Antígenos CD34/análisis , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/efectos de los fármacos , Recuento de Células , Relación Dosis-Respuesta a Droga , Células Endoteliales/enzimología , Células Endoteliales/inmunología , Femenino , Citometría de Flujo , Glicoproteínas/análisis , Humanos , Masculino , Persona de Mediana Edad , Péptidos/análisis , Proyectos Piloto , Agregación Plaquetaria/efectos de los fármacos , Pruebas de Función Plaquetaria , Estudios Prospectivos , Células Madre/enzimología , Células Madre/inmunología , Factores de Tiempo , Ultrasonografía , Estados Unidos , Vasodilatación/efectos de los fármacos

RESUMEN

OBJECTIVES: The aim of this study was to determine whether single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is an effective method of risk stratification for sudden cardiac death (SCD) in patients with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF)>35%. BACKGROUND: Most victims of SCD have an LVEF>35%. METHODS: The study population included 4,865 patients with CAD and LVEF>35% who underwent gated SPECT MPI. We used Cox proportional hazard modeling to examine the relationship between patient characteristics and SCD. RESULTS: The median age of the population was 63 years (25th, 75th percentile: 54, 71 years), and the median LVEF was 56% (25th, 75th percentile: 50%, 64%). The median follow-up for all patients was 6.5 years (25th, 75th percentile: 3.6, 9.3 years). During follow-up, there were 161 SCDs (3.3%). After multivariable adjustment, LVEF, the Charlson index, hypertension, smoking, antiarrhythmic drug therapy, and the summed stress score (SSS) were associated with SCD (all p<0.05). For each 3-U increase in the SSS, the hazard ratio for SCD was 1.13 (95% confidence interval: 1.04 to 1.23). The addition of perfusion data to the clinical history and LVEF was associated with increased discrimination for SCD events (c-index 0.728). Risk stratification with a derived SPECT nomogram did not result in statistically significant net reclassification improvement (p=0.26) or integrated discrimination improvement (p=0.38). CONCLUSIONS: Among patients with CAD and LVEF>35%, the extent of stress MPI perfusion defects is associated with an increased risk of SCD. Future large prospective studies should address the role of perfusion imaging in the identification of high-risk patients with LVEF>35% who might benefit from ICD implantation.

Asunto(s)

Enfermedad Coronaria/diagnóstico por imagen , Muerte Súbita Cardíaca/prevención & control , Imagen de Perfusión Miocárdica/métodos , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Volumen Sistólico , Tomografía Computarizada de Emisión de Fotón Único/métodos

RESUMEN

BACKGROUND: We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation. METHODS: Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge. RESULTS: Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS(2)) scores (0, 13%; 1, 14%; > or = 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98). CONCLUSION: Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS(2) score or bleeding risk.

Asunto(s)

Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/terapia , Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Warfarina/uso terapéutico , Síndrome Coronario Agudo/mortalidad , Anciano , Fibrilación Atrial/mortalidad , Estudios de Cohortes , Femenino , Fibrinolíticos , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

BACKGROUND: A hallmark of AIDS progression is a switch of cytokines from Th1 to Th2 in the plasma of patients. IL-12, a critical Th1 cytokine secreted by antigen presenting cells (APCs) is suppressed by Vpr, implicating it as an important virulence factor. We hypothesize that Vpr protein packaged in the virion may be required for disabling APCs of the first infected mucosal tissues. Consistent with this idea are reports that defects in the C-terminus of Vpr are associated with long-term non-progression. PRINCIPAL FINDINGS: Vpr RNA amplified from various sources was electroporated into monocyte-derived DC and IL-12 levels in supernatants were analyzed. The analysis of previously reported C-terminal Vpr mutations demonstrate that they do not alleviate the block of IL-12 secretion. However, a novel single conservative amino acid substitution, R90K, reverses the IL-12 suppression. Analysis of 1226 Vpr protein sequences demonstrated arginine (R) present at position 90 in 98.8%, with other substitutions at low frequency. Furthermore, none of sequences report lysine (K) in position 90. Vpr clones harboring the reported substitutions in position 90 were studied for their ability to suppress IL-12. Our data demonstrates that none of tested substitutions other than K relieve IL-12 suppression. This suggests a natural selection for sequences which suppress IL-12 secretion by DC and against mutations which relieve such suppression. Further analyses demonstrated that the R90K, as well as deletion of the C-terminus, directs the Vpr protein for rapid degradation. CONCLUSION: This study supports Vpr as an HIV virulence factor during HIV infection and for the first time provides a link between evolutionary conservation of Vpr and its ability to suppress IL-12 secretion by DC. DC activated in the presence of Vpr would be defective in the production of IL-12, thus contributing to the prevailing Th2 cytokine profile associated with progressive HIV disease. These findings should be considered in the design of future immunotherapies that incorporate Vpr as an antigen.

Asunto(s)

Productos del Gen vpr/metabolismo , Infecciones por VIH/metabolismo , Inmunosupresores/farmacología , Interleucina-12/metabolismo , Membrana Mucosa/virología , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/química , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/metabolismo , Células Dendríticas/metabolismo , Humanos , Membrana Mucosa/metabolismo , Mutación , Plásmidos/metabolismo , Estructura Terciaria de Proteína , ARN Viral/metabolismo , Transcripción Genética , Ubiquitina/metabolismo , Factores de Virulencia

RESUMEN

CONTEXT: The incidence and timing of sustained ventricular tachycardia or fibrillation (VT/VF) and its impact on outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) are poorly understood. OBJECTIVE: To evaluate the association of sustained VT/VF and its timing on the outcomes of patients presenting for primary PCI-an aim not prespecified in the APEX AMI trial. DESIGN, SETTING, AND PATIENTS: We studied 5745 STEMI patients presenting for primary PCI at 296 hospitals in 17 countries between July 13, 2004, and May 11, 2006, from the APEX AMI trial. We categorized them into 4 groups: no VT/VF; VT/VF any time; early VT/VF, before the end of cardiac catheterization; and late VT/VF, after the end of cardiac catheterization. MAIN OUTCOME MEASURE: Ninety-day total mortality. RESULTS: VT/VF occurred in 329 STEMI patients (5.7%) presenting for primary PCI. The majority of these occurred before the end of catheterization (n = 205, 64%), and 90% occurred within 48 hours of presentation with symptoms of STEMI. Clinical outcomes were worse in patients with vs those without VT/VF (90-day mortality, 23.2% vs 3.6%; adjusted HR, 3.63; 95% CI, 2.59-5.09), and outcomes were worse if the VT/VF occurred late instead of early (90-day mortality for early VT/VF, 17.2% [adjusted HR, 2.34; 95% CI, 1.44-3.80]; for late VT/VF, 33.3% [adjusted HR, 5.59; 95% CI, 3.71-8.43]; for no VT/VF, 3.6% [referent]). In multivariate analyses, factors associated with early VT/VF included pre-PCI thrombolysis in MI (TIMI) flow grade 0 (HR, 2.94; 95% CI, 1.93-4.47), inferior infarction (HR, 2.16; 95% CI, 1.58-2.93), total baseline ST deviation (HR, 1.39; 95% CI, 1.19-1.63), creatinine clearance (HR, 0.88; 95% CI, 0.83-0.94), Killip class greater than I (HR, 1.88; 95% CI, 1.29-2.76), baseline systolic blood pressure (HR, 0.92; 95% CI, 0.87-0.98), body weight (HR, 1.16; 95% CI, 1.04-1.29), and baseline heart rate greater than 70/min (HR, 1.10; 95% CI, 1.01-1.20) (c index, 0.75). Factors related to late VT/VF were systolic blood pressure (HR, 0.83; 95% CI, 0.76-0.91), ST resolution less than 70% (HR, 3.17; 95% CI, 1.60-6.28), baseline heart rate greater than 70/min (HR, 1.20; 95% CI, 1.08-1.33), total baseline ST deviation (HR, 1.43; 95% CI, 1.14-1.79), post-PCI TIMI flow less than grade 3 (HR, 2.09; 95% CI, 1.24-3.52), pre-PCI TIMI flow grade 0 (HR, 2.12; 95% CI, 1.20-3.75), and beta-blockers less than 24 hours (HR, 0.52; 95% CI, 0.32-0.85) (c index, 0.74). CONCLUSIONS: In this study, occurrence of VT/VF before or after the end of cardiac catheterization in patients presenting for primary PCI was associated with increased 90-day mortality.

Asunto(s)

Angioplastia Coronaria con Balón , Infarto del Miocardio/complicaciones , Taquicardia Ventricular/etiología , Fibrilación Ventricular/etiología , Distribución por Edad , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Taquicardia Ventricular/epidemiología , Resultado del Tratamiento , Fibrilación Ventricular/epidemiología

RESUMEN

BACKGROUND: Effective therapy for HIV-infected individuals remains an unmet medical need. Promising clinical trials with dendritic cell (DC)-based immunotherapy consisting of autologous DC loaded with autologous virus have been reported, however, these approaches depend on large numbers of HIV virions to generate sufficient doses for even limited treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: The present study describes a novel approach for RT-PCR amplification of HIV antigens. Previously, RT-PCR amplification of autologous viral sequences has been confounded by the high mutation rate of the virus which results in unreliable primer-template binding. To resolve this problem we developed a multiplex RT-PCR strategy that allows reliable strain-independent amplification of highly polymorphic target antigens from any patient and requires neither viral sequence data nor custom-designed PCR primers for each individual. We demonstrate the application of our RT-PCR process to amplify translationally-competent RNA encoding regions of Gag, Vpr, Rev and Nef. The products amplified using this method represent a complex mixture of autologous antigens encoded by viral quasispecies. We further demonstrate that DCs electroporated with in vitro-transcribed HIV RNAs are capable of stimulating poly-antigen-specific CD8+ T cell responses in vitro. CONCLUSION/SIGNIFICANCE: This study describes a strategy to overcome patient to patient viral diversity enabling strain-independent RT-PCR amplification of RNAs encoding sequence divergent quasispecies of Gag, Vpr, Rev and Nef from small volumes of infectious plasma. The approach allows creation of a completely autologous therapy that does not require advance knowledge of the HIV genomic sequences, does not have yield limitations and has no intact virus in the final product. The simultaneous use of autologous viral antigens and DCs may provoke broad patient-specific immune responses that could potentially induce effective control of viral loads in the absence of conventional antiretroviral drug therapy.

Asunto(s)

Células Dendríticas/inmunología , Genes Virales , Infecciones por VIH/terapia , VIH/genética , Inmunoterapia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Secuencia de Bases , Cartilla de ADN , Humanos