RESUMEN
BACKGROUND: In mouse models of allergic asthma, exposure to different allergens can trigger distinct inflammatory subtypes in the airways. We investigated whether this observation extends to humans. METHODS: We compared the frequency of sputum inflammatory subtypes between mild allergic asthma subjects (n = 129) exposed to different allergens in inhalation challenge tests. These tests were performed using a standardized protocol as part of clinical trials of experimental treatments for asthma, prior to drug randomization. Five allergen types were represented: the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae, ragweed, grass, and cat. RESULTS: Of 118 individuals with a sputum sample collected before allergen challenge (baseline), 45 (38%) had paucigranulocytic, 51 (43%) eosinophilic, 11 (9%) neutrophilic, and 11 (9%) mixed granulocytic sputum. Of note, most individuals with baseline paucigranulocytic sputum developed eosinophilic (48%) or mixed granulocytic (43%) sputum 7 hours after allergen challenge, highlighting the dynamic nature of sputum inflammatory subtype in asthma. Overall, there was no difference in the frequency of sputum inflammatory subtypes following challenge with different allergen types. Similar results were observed at 24 hours after allergen challenge. CONCLUSIONS: Unlike reported in mice, in humans the sputum inflammatory subtype observed after an allergen-induced asthma exacerbation is unlikely to be influenced by the type of allergen used.
Asunto(s)
Alérgenos/inmunología , Hipersensibilidad/diagnóstico , Hipersensibilidad/inmunología , Esputo/citología , Esputo/inmunología , Alérgenos/administración & dosificación , Animales , Asma/diagnóstico , Asma/inmunología , Pruebas de Provocación Bronquial , Granulocitos/inmunología , Granulocitos/metabolismo , Humanos , Inmunización , Inmunoglobulina E/inmunología , Ratones , Estudios Retrospectivos , Pruebas CutáneasRESUMEN
BACKGROUND: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.
Asunto(s)
Alérgenos/inmunología , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Asma/inmunología , Ligando de CD40/antagonistas & inhibidores , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Asma/metabolismo , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Células Dendríticas/inmunología , Eosinófilos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Linfocitos T/inmunología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.
Asunto(s)
Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Glandulares y Epiteliales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Neoplasias del Timo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Compuestos de Anilina/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia/efectos de los fármacos , Bencenosulfonatos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Hibridación Genómica Comparativa , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Indoles , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Glandulares y Epiteliales/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Piridinas/farmacología , Pirroles/farmacología , Interferencia de ARN , ARN Interferente Pequeño , Sorafenib , Sulfonamidas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Trasplante Heterólogo , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/metabolismoAsunto(s)
Asma/inmunología , Hipersensibilidad/inmunología , Interleucina-18/inmunología , Receptores de Interleucina-18/inmunología , Asma/metabolismo , Femenino , Humanos , Hipersensibilidad/metabolismo , Interleucina-18/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Interleucina-18/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Allergen inhalation causes early and late bronchoconstrictor responses, airway hyperresponsiveness and airway inflammation in allergic asthmatics. The role of airway inflammatory cells in causing allergen-induced bronchoconstriction and airway hyperresponsiveness is controversial. The objective of this study was to examine the relationships between allergen-induced increases in airway inflammatory cells, early and late bronchoconstrictor responses and methacholine airway hyperresponsiveness. METHODS: Allergen inhalation challenge was conducted in 50 allergic asthmatics. Changes in the forced expired volume in 1 s (FEV(1%) ) were followed for 7 h, induced sputum was obtained at 7 and 24 h, and the provocative concentration of methacholine causing a 20% fall in FEV(1) (MCh PC(20) ) was measured at 24 h. RESULTS: There was a significant negative correlation between the baseline methacholine PC(20) and baseline sputum eosinophils (r = -0.512, P = 0.0001). Allergen-induced changes in methacholine PC(20) were also significantly negatively correlated to allergen-induced change in sputum eosinophils at 24 h (r = -0.434, P = 0.002), but not to changes in any other inflammatory cells. There were no significant correlations between sputum eosinophils or other inflammatory cells and the allergen-induced early or late asthmatic responses. CONCLUSION: Allergen-induced increases in airway eosinophils in asthmatic dual responders may contribute to allergen-induced changes in methacholine PC(20) , but not the late asthmatic responses.
Asunto(s)
Asma/patología , Inflamación/patología , Esputo/inmunología , Alérgenos/farmacología , Broncoconstrictores , Eosinófilos/inmunología , Humanos , Cloruro de Metacolina/farmacologíaRESUMEN
BACKGROUND: The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-gamma (IFN-gamma) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. OBJECTIVE: This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. METHODS: Subjects were randomized to 7 days of placebo, 40 or 80 micro g ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. RESULTS: Ciclesonide 40 and 80 micro g significantly attenuated the late response and sputum eosinophils at 8 h post-allergen (P<0.05). Circulating IFN-gamma positive CD4+ lymphocytes decreased after allergen challenge with placebo (P<0.05), and this was inhibited by 40 micro g ciclesonide treatment (P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-gamma and IL-4-positive CD8(high) lymphocytes. The allergen-induced change of IFN-gamma/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. CONCLUSIONS: The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-gamma-positive CD4+ cells.
Asunto(s)
Asma/tratamiento farmacológico , Linfocitos T CD4-Positivos/inmunología , Glucocorticoides/administración & dosificación , Hipersensibilidad/tratamiento farmacológico , Pregnenodionas/administración & dosificación , Administración por Inhalación , Adulto , Alérgenos , Análisis de Varianza , Asma/inmunología , Biomarcadores/análisis , Pruebas de Provocación Bronquial , Linfocitos T CD8-positivos/inmunología , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Eosinófilos/inmunología , Femenino , Citometría de Flujo , Glucocorticoides/uso terapéutico , Humanos , Hipersensibilidad/inmunología , Interferón gamma/análisis , Interleucina-4/análisis , Recuento de Linfocitos , Masculino , Cloruro de Metacolina , Pregnenodionas/uso terapéutico , Esputo/inmunologíaAsunto(s)
Fatiga Muscular/fisiología , Músculo Esquelético/fisiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fenómenos Fisiológicos Musculoesqueléticos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
This 55-year-old man with known rheumatic mitral valve disease is modestly disabled achieving a VO2max of 72% and a maximal power output of 76% of the predicted normal. His capacity to exercise is limited by dyspnea due to a reduction in his capacity to breathe. Ipratropium bromide was initiated to maximize his expiratory flow and improve his ventilatory capacity. A trial of inhaled steroids produced no improvement. He was referred for rehabilitation and smoking cessation. A decision was made to continue surveillance, postponing mitral valve replacement.
Asunto(s)
Tolerancia al Ejercicio , Corazón/fisiopatología , Pulmón/fisiopatología , Insuficiencia de la Válvula Mitral/fisiopatología , Cardiopatía Reumática/fisiopatología , Sangre , Presión Sanguínea , Dióxido de Carbono/sangre , Dolor en el Pecho , Disnea/fisiopatología , Electrocardiografía , Prueba de Esfuerzo , Frecuencia Cardíaca , Humanos , Concentración de Iones de Hidrógeno , Pierna , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Oxígeno/sangre , Consumo de Oxígeno , Intercambio Gaseoso Pulmonar , Pruebas de Función Respiratoria , FumarRESUMEN
The hypothesis underlying the present study was that some of the variability in symptom intensity seen during acute bronchoconstriction may result from varying intensities of several stimuli yielding several sensations that can be identified by specific descriptive expressions (symptoms). A total of 232 subjects inhaled methacholine in doubling concentrations to a 20% decrease in FEV(1), or 64 mg/ml. The study identified the prevalence of dyspnea, nonspecific discomfort associated with the act of breathing, and 10 specific symptom expressions. Each symptom intensity was rated in Borg scale units. The contribution of the specific symptoms to the intensity of dyspnea is illustrated in the following equation (r = 0. 84): Dyspnea = 0.44 + 0.19 Difficult breathing + 0.41 Chest tightness + 0.20 Breathlessness + 0.14 Labored breathing + 0.11 Chest pain. Dyspnea was more intense with broncho-constriction, baseline pulmonary impairment, weight, and sex (being female). Dyspnea was less intense with age (being older) and as airway responsiveness to methacholine increased (p < 0.05 for all factors). Chest tightness and chest pain were at polar extremes on the discrimination scale, i.e., easily discriminated; chest tightness, difficult and labored breathing were not easily discriminated.
Asunto(s)
Broncoconstricción/fisiología , Adulto , Broncoconstrictores , Dolor en el Pecho , Disnea , Femenino , Humanos , Masculino , Cloruro de Metacolina , Respiración , Ruidos Respiratorios , SensaciónAsunto(s)
Fenómenos Fisiológicos Cardiovasculares , Ejercicio Físico/fisiología , Músculo Esquelético/metabolismo , Fenómenos Fisiológicos del Sistema Nervioso , Fenómenos Fisiológicos Respiratorios , Animales , Enfermedades Cardiovasculares/fisiopatología , Fatiga/fisiopatología , Humanos , Ácido Láctico/metabolismo , Consumo de Oxígeno , Enfermedades Respiratorias/fisiopatología , SensaciónRESUMEN
1. The present study examined the possibility that minimizing effort conflicts with minimizing energy expenditure at different velocities of muscle contraction during cycling. 2. Six normal subjects underwent incremental exercise on an electrically stabilized cycle ergometer. Power output increased by 45 W every 3 min to exhaustion at pedalling frequencies of 40, 60, 80 and 100 r.p.m. on separate days. Energy expenditure (oxygen uptake), leg effort and dyspnoea (Borg 0-10 scale) were measured in parallel at the end of each minute. 3. All six subjects completed 10 min of exercise achieving 180 W for all four pedalling frequencies. Two-way analysis of variance indicated that oxygen uptake (P < 0.0001), leg effort (P < 0.0001) and dyspnoea (P < 0.0001) increased with duration of exercise and power output; oxygen uptake (P < 0.0001) and leg effort (P < 0.05) were significantly different between pedalling frequencies; the interactions were not significant. Oxygen uptake was minimal at 60 r.p.m., and increased at both higher and lower pedalling frequencies. Both leg effort and dyspnoea were minimal at 80 r.p.m.; leg effort intensified at higher and lower pedalling frequencies; and dyspnoea was most intense at 100 r.p.m. 4. There was a conflict between minimization of energy expenditure and leg effort at power outputs less than 180 W. Minimizing effort occurred at the expense of an increase in energy expenditure.
Asunto(s)
Ciclismo/fisiología , Metabolismo Energético/fisiología , Músculo Esquelético/fisiología , Adulto , Disnea/fisiopatología , Prueba de Esfuerzo , Humanos , Masculino , Contracción Muscular/fisiología , Consumo de Oxígeno/fisiología , Mecánica Respiratoria/fisiología , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
Premature lactic acidosis during exercise in patients with chronic obstructive pulmonary disease (COPD) may play a role in exercise intolerance. In this study, we evaluated whether the early exercise-induced lactic acidosis in these individuals can be explained by changes in peripheral O2 delivery (O2). Measurements of leg blood flow by thermodilution and of arterial and femoral venous blood gases, pH, and lactate were obtained during a standard incremental exercise test to capacity in eight patients with severe COPD and in eight age-matched controls. No significant difference was found between the two groups in leg blood flow at rest or during exercise at the same power outputs. Blood lactate concentrations and lactate release from the lower limb were greater in COPD patients at all submaximal exercise levels (all P < 0.05). Leg D02 at a given power output was not significantly different between the two groups, and no significant correlation was found between this parameter and blood lactate concentrations. COPD patients had lower arterial and venous pH at submaximal exercise, and there was a significant positive correlation between venous pH at 40 W and the peak O2 uptake (r = 0.91, P < 0.0001). The correlation between venous pH and peak O2 uptake suggests that early muscle acidosis may be involved in early exercise termination in COPD patients. The early lactate release from the lower limb during exercise could not be accounted for by changes in peripheral O2. The present results point to skeletal muscle dysfunction as being responsible for the early onset of lactic acidosis in COPD.
Asunto(s)
Ejercicio Físico/fisiología , Hemodinámica/fisiología , Pierna/fisiología , Enfermedades Pulmonares Obstructivas/fisiopatología , Acidosis Láctica/patología , Anciano , Dióxido de Carbono/sangre , Humanos , Concentración de Iones de Hidrógeno , Ácido Láctico/sangre , Pierna/irrigación sanguínea , Enfermedades Pulmonares Obstructivas/complicaciones , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Flujo Sanguíneo Regional/fisiología , Pruebas de Función RespiratoriaRESUMEN
The aim of the study was to compare (1) the intensity of leg effort and dyspnea during exercise and (2) subjective limitations to performance in normal subjects, patients receiving medication for cardiac disorders, patients with pulmonary impairment, patients with pulmonary impairment who were also receiving cardiac medications, patients experiencing chest pain during exercise, and patients who had a reduced exercise capacity but did not have pulmonary impairment and were not receiving cardiac medication. Five hundred seventy-eight subjects rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain every minute (Borg scale) during an incremental exercise task (100 kpm/min each minute) to maximum work capacity on a cycle ergometer and following exercise indicated their subjective limitation by completing a simple questionnaire. Leg effort and dyspnea increased systematically with power output in a positively accelerating manner in all groups; both symptoms were significantly more intense in the impaired groups compared with the normal group at submaximal power outputs. In all groups, there was a significant relationship between symptom intensity at submaximal power outputs and the maximal power output achieved. Leg discomfort in combination with breathing discomfort was the predominant subjective limitation in all groups; chest pain in combination with leg and breathing discomfort was the major subjective limitation in individuals with angina. Activation of the sensory systems during exercise is accompanied by a perception of discomfort associated with the peripheral exercising muscles and discomfort with breathing; both discomfort associated with the exercising muscles and discomfort associated with breathing contribute to exercise limitation to a large degree in normal subjects and patients with cardiorespiratory diseases.
Asunto(s)
Tolerancia al Ejercicio , Cardiopatías/fisiopatología , Enfermedades Pulmonares/fisiopatología , Esfuerzo Físico/fisiología , Angina de Pecho/fisiopatología , Presión Sanguínea , Disnea/fisiopatología , Electrocardiografía , Prueba de Esfuerzo , Femenino , Volumen Espiratorio Forzado , Cardiopatías/tratamiento farmacológico , Frecuencia Cardíaca , Humanos , Pierna/fisiología , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Isquemia Miocárdica/fisiopatología , Dolor/fisiopatología , Resistencia Física , Trastornos Respiratorios/fisiopatología , Sensación , Encuestas y Cuestionarios , Volumen de Ventilación Pulmonar , Capacidad Vital , Evaluación de Capacidad de TrabajoRESUMEN
Eleven subjects performed a series of 30-s work bouts on a cycle ergometer at power outputs ranging from 20-120% of the work capacity (Wcap) achieved during an incremental cycle to exhaustion and estimated the intensity of several sensations (leg effort, muscle tension, muscle discomfort, muscle pain, and breathing discomfort) by using Borg's category-ratio scale (range 0-10 units). Leg effort was perceived as "just noticeable" at 31 +/- 15% Wcap, muscle tension was just noticeable at 31 +/- 16% Wcap, muscle discomfort was just noticeable at 47 +/- 21% Wcap, breathing discomfort was just noticeable at 52 +/- 19% Wcap, and muscle pain was just noticeable at 58 +/- 33% Wcap. The intensity of all sensations increased in a positively accelerating manner with increases in power output (P < 0.001). Above 60% Wcap, the intensity of leg effort and muscle tension exceeded the intensity of muscle pain (P < 0.01), and above 100% Wcap the intensity of muscle discomfort also exceeded the intensity of muscle pain (P < 0.01). At 120% Wcap, leg effort, muscle tension, and muscle discomfort were rated between "severe" and "very severe" (6.1 +/- 2.2, 6.4 +/- 2.0, and 5.6 +/- 2.1 Borg units, respectively), whereas muscle pain and breathing discomfort were rated between "moderate" and "somewhat severe" (3.6 +/- 2.1 and 3.3 +/- 1.9 Borg units, respectively). These results suggest that subjects have a perception of muscle pain during muscular work that is distinct from perceptions of leg effort, muscle tension, and muscle discomfort.
Asunto(s)
Ejercicio Físico/fisiología , Fatiga Muscular/fisiología , Sensación/fisiología , Adulto , Femenino , Humanos , Masculino , Análisis y Desempeño de TareasRESUMEN
The contribution of muscle strength to symptom intensity and work capacity was examined in normal individuals and patients with cardiorespiratory disorders. Respiratory muscle strengths (maximal inspiratory and expiratory pressures) and peripheral muscle strengths (leg extension, leg flexion, seated bench press, and seated row) were measured in 4,617 subjects referred for clinical exercise testing. Subjects then rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain (Borg scale) during an incremental exercise task (100 kpm/min each minute) to capacity on a cycle ergometer. Subjects were classified into groups on the basis of pulmonary function, drug therapy for cardiac disorders, and the presence of chest pain during exercise with electrocardiographic changes indicative of myocardial ischemia. Respiratory and peripheral muscle strengths, normalized for differences in age, sex, and height, were significantly reduced in patients with cardiorespiratory disorders compared with normal individuals. Muscle strength was a significant contributor to symptom intensity and work capacity in both health and disease; a two-fold increase in muscle strength was associated with a 25 to 30% decrease in the intensity of both leg effort and dyspnea and a 1.4- to 1.6-fold increase in work capacity. These results emphasize the need for an integrative approach in the assessment and therapeutic management of exercise intolerance, which considers the contribution of muscle weakness to excessive symptoms and reduced work capacity, in addition to the contribution of ventilatory, gas exchange, and circulatory impairments.
Asunto(s)
Tolerancia al Ejercicio , Cardiopatías/fisiopatología , Enfermedades Pulmonares/fisiopatología , Músculo Esquelético/fisiopatología , Angina de Pecho/complicaciones , Angina de Pecho/fisiopatología , Disnea/complicaciones , Disnea/fisiopatología , Femenino , Cardiopatías/complicaciones , Humanos , Articulación de la Rodilla/fisiopatología , Enfermedades Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Músculos Respiratorios/fisiopatologíaRESUMEN
To understand why someone is dyspneic during exercise, we need to follow the advice of Sir Francis Bacon: "No natural phenomenon can be adequately studied in itself alone, but to be understood must be considered as it stands connected with all of nature." In the present context, this implies the careful measurement of events related to metabolism, circulation, and respiration and of the associated sensory events as these systems adapt to the strain and stress of exercise.
Asunto(s)
Disnea , Prueba de Esfuerzo , Esfuerzo Físico , Disnea/etiología , Disnea/metabolismo , Disnea/fisiopatología , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Intercambio Gaseoso Pulmonar , Respiración , Trastornos Respiratorios/metabolismo , Trastornos Respiratorios/fisiopatología , Músculos Respiratorios/metabolismoRESUMEN
Adolescent idiopathic thoracic scoliosis may lead to severe pulmonary impairment and early death, but the responsible factors are poorly understood; pulmonary function is only weakly related to the angle of scoliosis. We performed a cross-sectional study using multivariate analysis to identify the individual and additive influence of different features of spinal deformity and nonstructural factors on pulmonary impairment. Pulmonary function was assessed by measuring lung volumes and diffusing capacity, with a priori selection of vital capacity (expressed as percentage of predicted, % VC) as the primary index of pulmonary impairment. Radiologic and physiologic measurements were made independently in 66 subjects who had not previously had spinal surgery. Angle of scoliosis (p = 0.01) was one of four features of spinal deformity associated with reduced % VC; greater number of vertebrae involved (p = 0.007), cephadal location of the curve (p = 0.04), and loss of the normal thoracic kyphosis (p = 0.002) made an equal and additive contribution to pulmonary impairment. Spinal deformity led to reductions in VC, primarily by reducing TLC. Spinal column rotation, respiratory muscle strength, and duration of the curvature were not related to pulmonary function (p > 0.05). We conclude that features of the spinal deformity are the major determinants of pulmonary impairment in idiopathic thoracic scoliosis but that the relationship between deformity and impairment is complex. The severity of pulmonary impairment cannot be inferred to a clinically useful extent from the angle of scoliosis alone.
Asunto(s)
Pulmón/fisiopatología , Escoliosis/fisiopatología , Vértebras Torácicas/patología , Adolescente , Adulto , Dióxido de Carbono/metabolismo , Estudios Transversales , Femenino , Capacidad Residual Funcional/fisiología , Humanos , Cifosis/patología , Lordosis/patología , Masculino , Flujo Espiratorio Máximo/fisiología , Oxígeno/sangre , Presión , Capacidad de Difusión Pulmonar/fisiología , Volumen Residual/fisiología , Escoliosis/patología , Capacidad Pulmonar Total/fisiología , Capacidad Vital/fisiologíaRESUMEN
The factors contributing to reduced work capacity (disability) in adolescent idiopathic thoracic scoliosis are poorly understood. We performed a cross-sectional study using multivariate analysis to identify the individual and additive influence of spinal deformity, pulmonary impairment, and muscular function on work capacity in 79 subjects with idiopathic scoliosis (angle of scoliosis 45 +/- 18.5 degrees, SD). Work capacity was measured using an incremental cycle test, and the cardiorespiratory response to exercise was compared with that of normal subjects. Work capacity was reduced (% Wcap, 86%; 95% CI 81.9 to 89.7), indicating significant disability. The % Wcap was unrelated to the nature and extent of spinal deformity (p > 0.05). Leg muscularity and pulmonary impairment had an additive influence on work capacity, the relationship with muscularity being the stronger of the two. Independently of muscularity and pulmonary impairment, a high heart rate response at submaximal work rates was also associated with a reduced work capacity. Ventilation was normal for metabolic demands. During exercise, the tidal volumes of scoliotic subjects were reduced in proportion to the vital capacity. We conclude that disability occurs with mild to moderate idiopathic scoliosis and appears to be related to a combination of reduced ventilatory capacity, reduced muscularity, and cardiovascular deconditioning. These findings suggest that physical activity should be encouraged in subjects with idiopathic scoliosis to maintain peripheral muscle and cardiovascular conditioning, thereby minimizing disability.