Ventricular function following myocardial infarction : the prognostic value of radionuclide ventriculography

Ventricular performance was assessed in one hundred consecutive patients recovering from their first myocardial infarction using the non-invasive technique of radionuclide ventriculography. This method was successfully performed in almost 100% of cases and repeated studies had a high degree of patient acceptability; the results were reproducible and easy to interpret and quantify with relative observer independence. Gated blood pool imaging performed prior to discharge from hospital revealed significant impairment of left ventricular function in the majority of patients, often when not clinically suspected. Those patients recovering from anterior infarction had greater reduction in left ventricular ejection fraction with a higher incidence of the more severe abnormalities of regional ventricular wall motion. A system of paradox imaging proved an accurate method for the detection of ventricular dyskinesis, present in 25% of all patients recovering from infarction. Subclinical right ventricular dysfunction occurred in over 40% of those recovering from inferior infarction and the variable degree of right ventricular necrosis contributed to enzymatic indices of infarct size accounting for the relative sparing of left ventricular function. Left ventricular failure and serious arrhythmia in the acute phase were both associated with marked reduction of ejection fraction in the convalescent phase. Low resting ejection fraction at discharge failed to improve in the subsequent year and was associated with the development of left ventricular failure, ventricular arrhythmia and sudden death. Reduction in ejection fraction during exercise testing performed four weeks after discharge had greater sensitivity and specificity than conventional electrocardiographic criteria in the prediction of the development of post-infarction angina which also carried a considerable risk of sudden death. The results of radionuclide ventriculography at rest and during exercise identified as "high risk" 11 of the 13 patients who were to die in the following year and proved more accurate than the Coronary Care Indices currently in use. The implications of these results are related to conventional clinical practice and the development of these and other radionuclide techniques to measure different parameters of ventricular function are discussed

Breathlessness Descriptors in Patients with Chronic Obstructive Pulmonary Disease Versus Congestive Heart Failure

This cross-sectional descriptive study investigated breathlessness (dyspnea) in stable patients with Chronic Obstructive Pulmonary Disease (COPD) and Congestive Heart Failure (CHF). The purpose of this study was (a) to characterize the most common terms COPD and CHF patients use to describe their breathing, (b) to identify the frequency of dyspnea in patients with COPD and CHF, and (c) to determine the intensity of dyspnea in these populations. A purposive sample of 60 patients, 30 with moderate to severe COPD and 30 patients with moderate to severe CHF, met the inclusion criteria and were enrolled in this study. The participants provided subjective information about their breathing discomfort by answering the Demographic Questionnaire and (b) Interview questionnaire developed by the researcher, (c) Endorsing terms from a list of descriptors, and (d) General dyspnea questionnaire from the Pulmonary Function Status and Dyspnea Questionnaire. Data was collected in an outpatient Pulmonary and CHF clinic of a Medical Center. The results indicated that patients with COPD and CHF chose different the terms to describe their breathing discomfort. There was no significant difference between the incidence (χ2 = 2.080, p = .195) and frequency (ṯ = 0.270, ք = .788) patients with COPD and CHF experience dyspnea. Participants with COPD reported significantly more dyspnea intensity ()than CHF in three different situations (COPD:CHF): (a) past year (ṯ = 2.426, ք = .018), (b) today (ṯ = 2.459, ք = .017), (c) most day-to-day activities COPD (ṯ = 2.499, ք = .015 ). The findings support the notion of previous studies regarding the breathlessness descriptors. Individuals with certain health conditions use (a) terms that are unique to describe their breathing experience, (b) choose more than one term (c) and use similar terms to describe their breathing experience. This study identified affective descriptors were among breathlessness descriptors in both groups. The frequency and intensity of dyspnea among COPD and CHF, had not been reported in previous studies, were identified

Advance in the Treatment of Pediatric Leukemia

The book gives an overview on the progress that has been made in the treatment of acute lymphoblastic leukemia (ALL), of acute and chronic myeloid leukemia (AML, CML) and of juvenile myelomonocytic leukemia (JMML). Leukemia is the most common malignant disease in children, and 80% of patients are diagnosed with ALL and 15–20% with AML, whereas CML and JMML are rather rare. Although ALL was considered an incurable disease until the early 1960s, with the availability of cytotoxic drugs and the start of clinical multicenter studies, ALL has become an almost curable disease with a survival rate exceeding 90 % in high-income countries. These impressive results have mainly been achieved by a deeper understanding of the genomic landscape of the disease and the introduction of risk stratifications based on genetic features and response to chemotherapy as determined by the presence or absence of minimal residual disease (MRD). Immunotherapies including bispecific T-cell Engagers (BiTEs), Chimeric Antigen Receptor (CAR) T cells, monoclonal antibodies and improvements in the outcome of allogeneic stem cell transplantation (HSCT) have shown impressive results in chemorefractory or relapsed patients, and it is anticipated that the cure rate can be further increased. For countries with less resources, therapies have to be adapted to increase survival as well. This book also updates on the progress made in the treatment of AML. As in ALL, risk classification based on genetic factors and response to chemotherapy is most important for therapy guidance. The book also provides updates and guidance for the treatment of CML and JMML

An account of the receipts and expenditures of the United States for the fiscal year ending June 30, 1875

Receipts and Expenditures. [2028] For fiscal 1874-1875: Indian expenses

Caracterización molecular de la Leucemia Aguda Linfoblástica B (LAL-B): Análisis genómico y funcional de la Leucemia Aguda Linfoblástica y un modelo in vitro de modificación genética dirigida.

Tesis por compendio de publicaciones[ES] Introducción: Los pacientes con leucemia aguda linfoblástica se caracterizan por la presencia de una serie de alteraciones genéticas que marcan el curso de la enfermedad. Estas alteraciones son la base de los actuales sistemas de clasificación y algunas de ellas han sido establecidas como importantes marcadores pronósticos. Además, el reciente desarrollo de las técnicas ómicas, como la secuenciación masiva y los ensayos de arrays, han posibilitado el estudio de un gran número de alteraciones genéticas recurrentes que podrían establecerse como nuevos marcadores de pronóstico, ayudando en la clasificación y estratificación del riesgo de los pacientes y en la identificación de predictores de la respuesta al tratamiento. A pesar de las altas tasas de supervivencia de estos enfermos, especialmente en la población pediátrica, un alto porcentaje de los pacientes siguen presentando recaídas, suponiendo así uno de los principales problemas en la clínica de la enfermedad, junto con la toxicidad al tratamiento. La recaída de la LAL-B se caracteriza por una gran heterogeneidad clonal, compuesta por un amplio número de alteraciones que podrían estar impulsando la evolución de la enfermedad. Aunque las recaídas se dan principalmente en los adultos, se ha reportado un alto porcentaje de niños, portadores del gen de fusión ETV6/RUNX1 que presentan recaídas tardías. Esta alteración es la traslación más frecuente de la infancia y aunque su papel en el desarrollo de la enfermedad parece estar claro, existe controversia acerca de la importancia de este en el mantenimiento del fenotipo leucémico. Mediante el desarrollo de esta tesis doctoral se emplea la combinación de las nuevas tecnologías ómicas y del sistema de edición genética CRISPR/cas9, con el objetivo de alcanzar una mayor comprensión de las anomalías genéticas de la LAL-B tanto en el diagnóstico como en la recaída. Además, el uso del sistema CRISPR/Cas9 proporcionará nuevos conocimientos sobre los mecanismos moleculares de las translocaciones involucradas en LAL-B, abriendo nuevas vías para el manejo de la enfermedad. Objetivos: I) Diseñar y validar un panel de NGS personalizado para la detección de las principales alteraciones moleculares asociadas con el riesgo genético de la LAL-B en el diagnóstico. II. Estudiar el perfil genético relacionado con la recaída de los pacientes de LAL-B a través del estudio integrativo de mutaciones y CNVs mediante el uso combinado de la NGS, MLPA y aCGH. III. Evaluar el papel del gen de fusión ETV6/RUNX1 en el mantenimiento del fenotipo leucémico mediante la generación de un modelo in vitro y un modelo de xenoinjerto. Los resultados de esta tesis se dividen en tres artículo publicados en revistas científicas, de acuerdo con los objetivos planteados: Artículo I: Montaño A. et al. J. Pers. Med. 2020, 10, 0137; doi:10.3390/jpm10030137. Artículo II: Forero-Castro M. & Montaño A. et al. Diagnostics 2020, 10(7), 455. doi:10.3390/diagnostics10070455. Artículo III: Montaño A. et al. Cells 2020, 9(1), 215. doi: 10.3390/cells9010215. Principales conclusiones: I) l uso de este panel personalizado de NGS permite detectar de forma rápida y eficaz las principales alteraciones genéticas presentes en LAL-B en un solo experimento (mutaciones, CNVs, aneuploidías y translocaciones). La aplicación del panel nos permitiría así acelerar el proceso de diagnóstico molecular de los pacientes, ayudando en la clasificación y estratificación de los enfermos, así como en la toma de decisiones terapéuticas. II) El presente estudio proporciona pruebas adicionales de que la clonalidad de la LAL-B es genéticamente dinámica desde el diagnóstico hasta la recaída. La combinación de análisis de NGS, aCGH y MLPA permitió además una mejor caracterización molecular del perfil genético en los pacientes con LAL-B en recaída. III) La eliminación del gen de fusión E/R reduce significativamente el potencial oncogénico de las células leucémicas (REH, E/R positivas) tanto in vivo como in vitro. Las células E/R KO también mostraron una mayor sensibilidad a los fármacos (copanlisib solo y en combinación con prednisolona), lo que sugiere que la expresión E/R podría estar implicada en la resistencia a la prednisolona observada en algunos pacientes. Estos resultados sugieren que el gen de fusión E/R juega un papel importante en el mantenimiento del fenotipo leucémico. Por consiguiente, el gen de fusión podría convertirse en una posible diana terapéutica específica para estos pacientes con la que se obtendrían mejores tasas de respuesta

Structure, Activity, and Function of Protein Methyltransferases

This collection of review articles describes the structure, function and mechanism of individual protein methyltransferase enzymes including protein lysine methyltransferases, protein arginine methyltransferases, and also the less abundant protein histidine methyltransferases and protein N-terminal end methyltransferases. The topics covered in the individual reviews include structural aspects (domain architecture, homologs and paralogs, and structure), biochemical properties (mechanism, sequence specificity, product specificity, regulation, and histone and non-histone substrates), cellular features (subcellular localization, expression patterns, cellular roles and function, biological effects of substrate protein methylation, connection to cell signaling pathways, and connection to chromatin regulation) and their role in diseases. This review book is a useful resource for scientists working on protein methylation and protein methyltransferases and those interested in joining this emerging research field

Using Mathematical Modelling and Electrochemical Analysis to Investigate Age‐Associated Disease

People are living longer. With this rise in life expectancy, a concomitant rise in morbidity in later life is observed; with conditions including cardiovascular disease (CVD), and cancer. However, ageing and the pathogenesis of age related disease, can be difficult to study, as the ageing process is a complex process, which affects multiple systems and mechanisms. The aim of this research was two‐fold. The first aim was to use mathematical modelling to investigate the mechanisms underpinning cholesterol metabolism, as aberrations to this system are associated with an increased risk for CVD. To better understand cholesterol from a mechanistic perspective, a curated kinetic model of whole body cholesterol metabolism, from the BioModels database, was expanded in COPASI, to produce a model with a broader range of mechanisms which underpin cholesterol metabolism. A range of time course data, and local and global parameter scans were utilised to examine the effect of cholesterol feeding, saturated fat feeding, ageing, and cholesterol ester transfer protein (CETP) genotype. These investigations revealed: the model behaved as a hypo‐responder to cholesterol feeding, the robustness of the cholesterol biosynthesis pathway, and the impact CETP can have on healthy ageing. The second aim of this work was to use electrochemical techniques to detect DNA methylation within the engrailed homeobox 1 (EN1) gene promoter, which has been implicated in cancer. Hypermethylation of this gene promoter is often observed in a diseased state. Synthetic DNA, designed to represent methylated and unmethylated variants, were adsorbed onto a gold rotating disk electrode for electrochemical analysis by 1) electrochemical impedance spectroscopy (EIS), 2) cyclic voltammetry (CV) and 3) differential pulse voltammetry (DPV). The technique was then applied to bisulphite modified and asymmetrically amplified DNA from the breast cancer cell line MCF‐7. Results indicated that electrochemical techniques could detect DNA methylation in both synthetic and cancer derived DNA, with EIS producing superiorresults. These non‐traditional techniques ofstudying age related disease were effective for the investigation of cholesterol metabolism and DNA methylation, and this work highlights how these techniques could be used to elucidate mechanisms or diagnose/monitor disease pathogenesis, to reduce morbidity in older peopl

The nutritional risks of children with cancer

Nutrition is a major concern in paediatric cancer, increasing the risk of co-morbidities, affecting tolerance of therapies and influencing survival. Despite this, very few studies have aimed to identify the nutritional risks of children treated for cancer in the western world. A unique retrospective study was therefore proposed to assess the degree of nutritional risk in paediatric cancer using the need for nutrition support (NS) as a proxy for high nutritional risk. Of 168 patients, seventy four (44%) required NS of whom 50 (67%) and 24 (33%) had solid and haematological malignancies. These findings underline the common need for NS in this childhood cancer cohort. A prospective study was consequently designed to assess the effect of cancer and its treatment on nutritional status, using commonly used assessment techniques. Measurements were taken regularly at six time points over a period of up to 18 months. 26 patients, 18 (69%) male and 8 (31%) female (median age 5.1; IQR 2.3, 7.9) volunteered for the study. At recruitment and during the first three months of treatment, those with solid tumour demonstrated nutritional deprivation, low BMI (median 25.5, IQR 5.5-60.5; median 18.0, IQR 7.5-54.2 respectively), low fat mass %(median 76.3, IQR 48.5-99.1; median 70.8, IQR 62.6-124.8 respectively), low energy intake (median kcal/d 1200, IQR 866-1970; median 1305 kcal/d, IQR 901-1488) and a high need for NS. In contrast, those with haematological cancer demonstrated an excess BMI (median 66.0, IQR 41.5-82.2; median 79.5; IQR 70- 94.2 respectively), high fat mass % (median 102.0, IQR 78.6- 153.0; median 129.4, IQR 96.5-202.6,respectively) and excessive energy intake (median kcal/d 2076; IQR 1453-2525, median kcal/d 1078, IQR 919-1206 respectively) These results suggest that children undergoing cancer therapy are at high risk of both undernutrition and obesity and they indicate apparent differences in nutritional risk according to diagnosis and treatment.sub_dnbsunpub1587_ethesesunpu