RESUMEN
BACKGROUND: XRCC1 (X-ray repair cross-complementing group 1) plays a central role in the DNA base excision repair mechanism. Single nucleotide polymorphisms (SNPs) in the XRCC1 gene are thought to modulate DNA repair capacity and have been linked to cancer risk in several studies. MATERIALS AND METHODS: We conducted a case-control study comprising 217 cervical samples, including 103 cervical carcinomas and 114 normal tissue samples. Cervical samples were genotyped for two XRCC1 SNPs (Arg194Trp and Arg399Gln) by PCR-RFLPs. RESULTS: Subjects carrying heterozygous Arg399Gln or the combined Gln399Gln + Arg399Gln variant genotypes had a significantly reduced risk for cervical cancer development. In addition, the 194Arg-399Gln haplotype was also found to be associated with a decreased risk for cervical carcinoma. CONCLUSION: Our findings suggest that XRCC1 genotypes and haplotypes contribute in reducing the risk for cervical cancer development. Furthermore, genetic susceptibility conferred by Arg399Gln polymorphism operates independently of human papillomavirus infection of cervical tissue.
Asunto(s)
Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias del Cuello Uterino/genética , Adulto , Alelos , Argentina , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/genética , Riesgo , Neoplasias del Cuello Uterino/virología , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
In some asthmatics deep inspiration causes a sustained bronchoconstration, which is dependent on Ca2+ uptake. Inhaled diuretics protect against bronchoconstriction induced by a variety of indirect stimuli, by inhibiting the ionic fluxes involving Ca2+ uptake across the cell membrane of airway epithelium. The aim of this study was therefore to investigate the protective effect of inhaled furosemide on the bronchoconstriction induced by deep inspiration in asthma and to compare it with the effect of acetazolamide, an inhibitor of carbonic anhydrase devoid of effect on ion cotransport but possessing inhibitory effects on chloride ion influx and Na+/K+ exchange. The study was carried out on three different study days according to a randomized, double-blind, placebo-controlled, crossover design. Nine non smoking asthmatic subjects first performed a series of 9 controlled deep inspirations to TLC followed by forced expirations to RV within 20 min, which caused a decrease of FEV1 > 20% from baseline. Two hours later, the subjects inhaled either furosemide (40 mg), or acetazolamide (500 mg), or saline (placebo) in random order, and then two more deep-inspiration challenges were performed after 30 and 140 mins. The progressive percent decrement of FEV1 caused by deep-inspiration challenge was taken as an index of bronchoconstriction. Bronchoconstriction was significantly blunted at 30 mins, but not 140 mins, after inhaling furosemide (p < 0.01) or acetazolamide (p < 0.05) compared to control. We interpret these results as due to a modulation of ionic fluxes across the smooth muscle cell membrane afforded by inhaled furosemide and acetazolamide.
Asunto(s)
Acetazolamida/farmacología , Asma/fisiopatología , Broncoconstricción/efectos de los fármacos , Diuréticos/farmacología , Furosemida/farmacología , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
To evaluate whether the interindividual differences in dyspnoea perceived by asthmatic subjects for the same level of airway narrowing could depend on different changes in respiratory drive, we assessed the relationship between changes in airway calibre, changes in neuromuscular output, and dyspnoea rate during progressive bronchoconstriction induced by methacholine. We studied 18 asymptomatic asthmatic subjects (aged 18-36 yrs; 11 males and 7 females) with normal lung function. Dyspnoea (Borg scale), mouth occlusion pressure (P0.1), and forced expiratory volume in one second (FEV1) were measured at baseline and after inhalation of aerosols of doubling concentrations of methacholine (MCh). The progressive bronchoconstriction induced by MCh was associated with a progressive increase both of P0.1 and dyspnoea. Dyspnoea score was linearly related either to the fall in FEV1, or to the increase in P0.1. However, the slope values of the relationship between dyspnoea score and the corresponding percent fall in FEV1 showed a large interindividual variability (0.05-0.32; coefficient of variability (CoV) 43%). By contrast, the slope values of the relationship between dyspnoea score and the corresponding percent increase in P0.1 ranged 0.02-0.05 (CoV = 14%), indicating a more homogeneous response to dyspnoea for the same change in P0.1. At the highest MCh concentration, the dyspnoea score was linearly related to the corresponding change in P0.1 (r = 0.91; p < 0.01), but not to the corresponding percentage fall in FEV1 (r = 0.28). These results show that the interindividual differences in dyspnoea perceived by asthmatic subjects for the same level of airway narrowing are associated with different changes in respiratory drive during bronchoconstriction.
Asunto(s)
Asma/fisiopatología , Disnea/complicaciones , Adolescente , Adulto , Asma/complicaciones , Pruebas de Provocación Bronquial , Constricción Patológica/complicaciones , Constricción Patológica/fisiopatología , Disnea/fisiopatología , Femenino , Humanos , Masculino , Pruebas de Función Respiratoria , Mecánica Respiratoria/fisiologíaRESUMEN
Possible mechanisms involved in inhaled sodium metabisulfite (MBS)-induced bronchoconstriction include cholinergic reflex and release of tachykinins from sensory nerve endings. Tachykinins are potent bronchoconstrictors cleaved and inactivated by neutral endopeptidase (NEP) in the airways. To investigate the role of tachykinins in airway response to MBS, we assessed the effect of NEP-inhibitor thiorphan on airway response to MBS in nine nonatopic, nonasthmatic subjects. Two inhalational challenges with doubling doses of MBS (0.03 to 16 mumol) were performed 3 d apart. Ten minutes before MBS challenge, subjects randomly inhaled either thiorphan (1.25 mg) or placebo according to a double-blind cross-over design. Airflow at 30% of vital capacity (V30p) from partial expiratory flow-volume curves was measured at baseline, 10 min after thiorphan or placebo, and 2 min after each MBS dose. The dose of MBS causing 40% fall in V30p (PD40V30p) was calculated. Neither thiorphan nor placebo affected baseline airway caliber. Thiorphan caused a leftward shift of the dose-response curve to MBS. After placebo a measurable PD40V30p was obtained in four of nine subjects. In these subjects PD40V30p fell significantly after thiorphan inhalation. Four of five subjects who did not exhibit PD40V30p after placebo showed measurable PD40V30p after thiorphan. Percent fall in V30p caused by highest dose of MBS was significantly greater after thiorphan compared with placebo (55.9 +/- 4.6% versus 30.8 +/- 5.6%; mean +/- SE; p < 0.001). Results of this study demonstrate that the NEP-inhibitor thiorphan increases MBS-induced bronchoconstriction in normal subjects, suggesting that tachykinins are involved in airway responses to inhaled MBS.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Broncoconstrictores/administración & dosificación , Neprilisina/antagonistas & inhibidores , Sulfitos/administración & dosificación , Tiorfan/administración & dosificación , Adulto , Aerosoles , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Sinergismo Farmacológico , Humanos , Masculino , Valores de Referencia , Pruebas de Función Respiratoria , Factores de TiempoRESUMEN
To examine the effect of inhaled platelet-activating factor (PAF) on airway sensitivity and on maximal airway narrowing, we measured airway response to doubling concentrations of methacholine (MCh) 48 h before and 48 h after inhalation of 10, 50 and 100 micrograms of PAF in six nonatopic, nonasthmatic subjects. The forced expiratory volume in one second (FEV1) and airflow at 30 percent of vital capacity (V30) from partial forced expiration were used to assess changes in airway calibre. Inhalation of PAF caused only minor changes in FEV1. In contrast, inhalation of 100 micrograms of PAF caused a significant fall in V30 from 2.64 +/- 0.35 to 1.35 +/- 0.43 l.min-1 (p < 0.05). Two days after PAF inhalation a leftward shift of the concentration-response curve to MCh was observed. The MCh concentration causing a 20% fall in FEV1 (PC20FEV1) was 11.25 +/- 1.78 and 2.38 +/- 1.29 mg.ml-1 (geometric mean +/- GSEM; p < 0.05) before and after PAF inhalation, respectively. PAF did not affect the maximal airway response to MCh. The maximum percentage fall in FEV1 was 36.2 +/- 1.9% at baseline and 37.6 +/- 1.8% after PAF inhalation. Likewise, maximum percentage change in V30 was 72.8 +/- 3.7% at baseline and 73.6 +/- 3.4% after PAF inhalation. The results of this study show that PAF inhalation increases airway sensitivity without altering the maximal bronchoconstrictive response to MCh in normal subjects.
Asunto(s)
Bronquios/efectos de los fármacos , Broncoconstricción/efectos de los fármacos , Cloruro de Metacolina/farmacología , Factor de Activación Plaquetaria/farmacología , Administración por Inhalación , Adulto , Hiperreactividad Bronquial/fisiopatología , Pruebas de Provocación Bronquial , Relación Dosis-Respuesta a Droga , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Flujo Espiratorio Máximo/efectos de los fármacos , Curvas de Flujo-Volumen Espiratorio Máximo/efectos de los fármacos , Cloruro de Metacolina/administración & dosificación , Ápice del Flujo Espiratorio/efectos de los fármacos , Factor de Activación Plaquetaria/administración & dosificación , Ventilación Pulmonar/efectos de los fármacos , Capacidad Pulmonar Total/efectos de los fármacos , Capacidad Vital/efectos de los fármacosRESUMEN
To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.