ABSTRACT
Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and sarcolemmal Na+/Ca2+ exchanger (NCX1) structures are involved in heart cell Ca2+ homeostasis. Previous studies have shown discrepancies in their function and expression in heart failure. The goal of this study was to evaluate heart function and hypertrophied muscle Ca2+-handling protein behavior under pressure overload. Twenty male Wistar rats were divided into two groups: Aortic stenosis (AoS), induced by a clip placed at the beginning of the aorta, and Control (Sham). After 18 weeks, heart function and structure were evaluated by echocardiogram. Myocardial function was analyzed by isolated papillary muscle (IPM) at basal condition and Ca2+ protein functions were evaluated after post-pause contraction and blockage with cyclopiazonic acid in IPM. Ca2+-handling protein expression was studied by western blot (WB). Echocardiogram showed that AoS caused concentric hypertrophy with enhanced ejection fraction and diastolic dysfunction inferred by dilated left atrium and increased relative wall thickness. IPM study showed developed tension was the same in both groups. AoS showed increased stiffness revealed by enhanced resting tension, and changes in Ca2+ homeostasis shown by calcium elevation and SERCA2a blockage maneuvers. WB revealed decreased NCX1, SERCA2a, and phosphorylated phospholambam (PLB) on serine-16 in AoS. AoS had left ventricular hypertrophy and diastolic dysfunction compared to Sham; this could be related to our findings regarding calcium homeostasis behavior: deficit in NCX1, SERCA2a, and phosphorylated PLB on serine-16.
Subject(s)
Animals , Male , Rats , Calcium/metabolism , Ventricular Remodeling , Rats, Wistar , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , HomeostasisABSTRACT
Previous genetic association studies have overlooked the potential for biased results when analyzing different population structures in ethnically diverse populations. The purpose of the present study was to quantify this bias in two-locus association studies conducted on an admixtured urban population. We studied the genetic structure distribution of angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen methionine/threonine (M/T) polymorphisms in 382 subjects from three subgroups in a highly admixtured urban population. Group I included 150 white subjects; group II, 142 mulatto subjects, and group III, 90 black subjects. We conducted sample size simulation studies using these data in different genetic models of gene action and interaction and used genetic distance calculation algorithms to help determine the population structure for the studied loci. Our results showed a statistically different population structure distribution of both ACE I/D (P = 0.02, OR = 1.56, 95 percent CI = 1.05-2.33 for the D allele, white versus black subgroup) and angiotensinogen M/T polymorphism (P = 0.007, OR = 1.71, 95 percent CI = 1.14-2.58 for the T allele, white versus black subgroup). Different sample sizes are predicted to be determinant of the power to detect a given genotypic association with a particular phenotype when conducting two-locus association studies in admixtured populations. In addition, the postulated genetic model is also a major determinant of the power to detect any association in a given sample size. The present simulation study helped to demonstrate the complex interrelation among ethnicity, power of the association, and the postulated genetic model of action of a particular allele in the context of clustering studies. This information is essential for the correct planning and interpretation of future association studies conducted on this population
Subject(s)
Humans , Male , Female , Racial Groups , Hypertension/genetics , Polymorphism, Genetic/genetics , Renin-Angiotensin System , Alleles , Analysis of Variance , Chi-Square Distribution , Cluster Analysis , Genotype , Hypertension/ethnology , Models, Genetic , Peptidyl-Dipeptidase A , Polymerase Chain ReactionABSTRACT
Los casos de carcinoma cervicouterino se diagnostican en la mayoría de las pacientes en etapas localmente avanzadas. Esto evita el abordaje quirúrgico. La quimioterapia combinada neoadyuvante ha demostrado reducción tumoral en más de la mitad de los casos tratados. En el Instituto Nacional de Cancerología, elaboramos un estudio fase II con objeto de determinar la eficacia y la toxicidad de la combinación de ifosfamida+mesna+carboplatino. También se evaluó la posibilidad de intervenir quirúrgicamente a las enfermas con carcinoma cervicouterino etapa IIB. Se incluyeron 20 pacientes sin tratamiento previo y con edad promedio de 42 años. Todas recibieron tres ciclos de quimioterapia cada cuatro semanas con carboplatino 300 mg/m² el día 1+ifosfamida 3g/m²/día por dos días en infusión contínua de 24 horas; mesna 600mg por vía intravenosa (bolo) directo antes de ifosfamida; 3,000 mg en la solución de la ifosfamida en infusión de 24 horas por dos días. Al término de ésta se administró 1,500 mg de mesna en 1,00 ml de solución glucosada en infusión de 12 horas. Se obtuvieron cuatro respuestas completas y nueve parciales; tres pacientes cursaron con enfermedad estable y cuatro progresaron. En dos enfermas sometidas a cirugía, los especímenes mostraron: carcinoma in situ residual en una mujer y en la otra no hubo actividad tumoral. De 18 pacientes que recibieron radioterapia posterior a la quimioterapia, 13 tuvieron respuesta completa, una mostró respuesta parcial y cuatro progresaron. La toxicidad para 54 ciclos de quimioterapia fue predominantemente medular; neutropenia grado 1-2 (6 por ciento), grado 3-4 (62 por ciento); plaquetopenia grado 0 (90 por ciento), grado 1-2 (44 por ciento) y grado 3 (4 por ciento). No se observó ningún proceso séptico asociado a la neutropenia. Se presentó emesis grado 2-3 en el 42 por ciento y alopecia grado 3 en el 75 por ciento. El seguimiento promedio para todas la pacientes fue de 12 meses. El intervalo libre de progresión en 14 casos con respuesta completa (13 con quimioterapia+radioterapia y uno con quimioterapia+cirugía) fue de 14.3 meses promedio (extremos 6-19 meses). Los resultados obtenidos con esta combinación confirman un alto índice de respuestas objetivas (65 por ciento) y completas (20 por ciento) con toxicidad moderada. La quimioterapia neoadyuvante puede reducir suficientemente el volumen tumoral; esto permite la cirugía en pacientes tradicionalmente consideradas con enfermedad irresecable