RESUMEN
Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.
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Factores de Intercambio de Guanina Nucleótido/genética , Inositol Polifosfato 5-Fosfatasas/genética , Mutación , Fenotipo , Fosfoglicerato-Deshidrogenasa/genética , Degeneraciones Espinocerebelosas/genética , Adolescente , Adulto , Animales , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Proteómica , Degeneraciones Espinocerebelosas/patología , Pez CebraRESUMEN
Autophagy is commonly described as a cell survival mechanism and has been implicated in chemo- and radioresistance of cancer cells. Whether ionizing radiation induced autophagy triggers tumor cell survival or cell death still remains unclear. In this study the autophagy related proteins Beclin1 and ATG7 were tested as potential targets to sensitize colorectal carcinoma cells to ionizing radiation under normoxic, hypoxic and starvation conditions. Colony formation, apoptosis and cell cycle analysis revealed that knockdown of Beclin1 or ATG7 does not enhance radiosensitivity in HCT-116 cells. Furthermore, ATG7 knockdown led to an increased survival fraction under oxygen and glutamine starvation, indicating that ionizing radiation indeed induces autophagy which, however, leads to cell death finally. These results highlight that inhibition of autophagic pathways does not generally increase therapy success but may also lead to an unfavorable outcome especially under amino acid and oxygen restriction.
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Apoptosis/efectos de la radiación , Autofagia/efectos de la radiación , Neoplasias Colorrectales/patología , Radiación Ionizante , Proteína 7 Relacionada con la Autofagia/metabolismo , Beclina-1/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Glutamina/deficiencia , Humanos , Oxígeno/farmacologíaRESUMEN
AIM: To explore nurse specialists' experiences of change and influence on practice two years after graduating with a postgraduate degree. BACKGROUND: In the absence of further study opportunities for nurses in their own country, a master's degree was introduced to train the first group of nurse specialists in Mozambique. DESIGN: Within a hybrid evaluation framework an exploratory, sequential mixed methods design was followed. METHODS: Qualitative data from focus group interviews with nurse specialists (N = 12) led to five thematic data sets from which survey questions were formulated for the sequential quantitative component. FINDINGS: "Change expectations", "Ambiguous practice environments", "Feeling powerless", "Having some influence" and "Workplace support" were emergent themes from interview data. Areas of positive change occurred in research (100%) and the use of evidence (88.9%) and involvement in decision-making (77.8%). For some change did not happen as anticipated-reasons included lack of nurse mentors to support new graduates (55.6%); lesser respect compared with doctors (44.4%) and poor understanding of the value of a master's degree (44.4%). Improvements in service quality and elevating the status of nursing were areas of greatest influence (77.8%). CONCLUSION: Several enabling and limiting factors were identified in the experiences of change and influence on practice of newly qualified nurse specialists. Tacit change with respect to the value of the degree in improving the status of nursing seems not to have affected nurse specialists' own ability and power to influence practice. Improved postgraduate capacity on its own does not empower nurses in their role as specialists. IMPACT: The findings point to a two-tiered strategy to be developed to dismantle barriers to the empowerment and advancement of nurse specialists. The identification of designated nurse mentors is essential to induct and sustain newly graduated nurse specialists. A clear research policy should be developed that supports the conduct of relevant research and the use of evidence in specialist practice.
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Competencia Clínica/estadística & datos numéricos , Educación de Postgrado en Enfermería/estadística & datos numéricos , Enfermeras Especialistas/educación , Enfermeras Especialistas/estadística & datos numéricos , Rol de la Enfermera/psicología , Personal de Enfermería/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mozambique , Investigación Metodológica en Enfermería , Pobreza , Encuestas y CuestionariosRESUMEN
Hypoxia-induced resistance of tumor cells to therapeutic treatment is an unresolved limitation due to poor vascular accessibility and protective cell adaptations provided by a network, including PERK, NRF2, and HIF signaling. All three pathways have been shown to influence each other, but a detailed picture remains elusive. To explore this crosstalk in the context of tumor therapy, we generated human cancer cell lines of pancreatic and lung origin carrying an inducible shRNA against NRF2 and PERK. We report that PERK-related phosphorylation of NRF2 is only critical in Keap1 wildtype cells to escape its degradation, but shows no direct effect on nuclear import or transcriptional activity of NRF2. We could further show that NRF2 is paramount for proliferation, ROS elimination, and radioprotection under constant hypoxia (1% O2), but is dispensable under normoxic conditions or after reoxygenation. Depletion of NRF2 does not affect apoptosis, cell cycle progression and proliferation factors AKT and c-Myc, but eliminates cellular HIF-1α signaling. Co-IP experiments revealed a protein interaction between NRF2 and HIF-1α and strongly suggest NRF2 as one of the cellular key factor for the HIF pathway. Together these data provide new insights on the complex role of the PERK-NRF2-HIF-axis for cancer growth.
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Hipoxia de la Célula/genética , Neoplasias Pulmonares/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/genética , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pancreáticas/patología , Transducción de Señal , TransfecciónRESUMEN
The disulfide isomerase ERp57, originally found in the endoplasmic reticulum, is located in multiple cellular compartments, participates in diverse cell functions and interacts with a huge network of binding partners. It was recently suggested as an attractive new target for cancer therapy due to its critical role in tumor cell proliferation. Since a major bottleneck in cancer treatment is the occurrence of hypoxic areas in solid tumors, the role of ERp57 in cell growth was tested under oxygen depletion in the colorectal cancer cell line HCT116. We observed a severe growth inhibition when ERp57 was knocked down in hypoxia (1% O2) as a consequence of downregulated c-Myc, PLK1, PDPK1 (PDK1) and AKT (PKB). Further, irradiation experiments revealed also a radiosensitizing effect of ERp57 depletion under oxygen deprivation. Compared to ERp57, we do not favour PDPK1 as a suitable pharmaceutical target as its efficient knockdown/chemical inhibition did not show an inhibitory effect on proliferation.
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Proteínas de Ciclo Celular/metabolismo , Neoplasias del Colon/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Hipoxia Tumoral , Apoptosis , Proliferación Celular , Neoplasias del Colon/genética , Neoplasias del Colon/radioterapia , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Oxígeno/metabolismo , Proteína Disulfuro Isomerasas/genética , Transducción de Señal , Quinasa Tipo Polo 1RESUMEN
Upon ER stress cells activate the unfolded protein response through PERK, IRE1 and ATF6. Remarkable effort has been made to delineate the downstream signaling of these three ER stress sensors after activation, but upstream regulation at the ER luminal site still remains mostly undefined. Here we report that the thiol oxidoreductase PDI is mandatory for activation of the PERK pathway in HEK293T as well as in human pancreatic, lung and colon cancer cells. Under ER stress, depletion of PDI selectively abrogated eIF2α phosphorylation, induction of ATF4, CHOP and even BiP. Furthermore, we could demonstrate that PDI prevented degradation of activated PERK by the 26S proteasome and therefore contributes to maintained PERK signaling. As a result of decreased PERK activity, PDI depleted cells showed an increased vulnerability to ER stress induced by chemicals or ionizing radiation in 2D as well as in 3D culture models. We conclude that PDI is an obligatory regulator of the PERK pathway with future therapy implications.
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Estrés del Retículo Endoplásmico/fisiología , Oxidorreductasas/metabolismo , Transducción de Señal/fisiología , eIF-2 Quinasa/metabolismo , Células A549 , Apoptosis/fisiología , Línea Celular , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Células HCT116 , Células HEK293 , Humanos , Neoplasias/metabolismo , Fosforilación/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteína Disulfuro Isomerasas/metabolismoRESUMEN
Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) that results in transient suppression of protein translation to allow recovery but leads to cell death when stress cannot be resolved. Central to initiation of the UPR is the activation of the ER transmembrane kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Here we report that the thiol oxidoreductase ERp57 and protein disulfide isomerase-A1 (PDI), which belong to the same family of luminal ER oxidoreductases, have strikingly opposing roles in the regulation of PERK function. In HCT116 colon carcinoma cells, lentiviral depletion of ERp57 resulted in oxidation of PDI and activation of PERK, whereas depletion or chemical inhibition of PDI reduced PERK signaling and sensitized the cancer cells to hypoxia and ER stress. We conclude that oxidized PDI acts as a PERK activator, whereas ERp57 keeps PDI in a reduced state in the absence of ER stress. Thus, our study defines a new interface between metabolic redox signaling and PERK-dependent activation of the UPR and has the potential to influence future cancer therapies that target PERK signaling.
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Procolágeno-Prolina Dioxigenasa/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Respuesta de Proteína Desplegada/fisiología , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Apoptosis/genética , Apoptosis/fisiología , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/fisiología , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Células HCT116 , Humanos , Oxidación-Reducción , Procolágeno-Prolina Dioxigenasa/genética , Proteína Disulfuro Isomerasas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Respuesta de Proteína Desplegada/genética , eIF-2 Quinasa/genéticaRESUMEN
STUDY OBJECTIVE: The efficacy of using impulse oscillometry (IOS) as an indirect measure of airflow obstruction compared to spirometry after exercise challenges in the evaluation of exercise-induced bronchoconstriction (EIB) has not been fully appreciated. The objective was to compare airway responses following room temperature and cold temperature exercise challenges, and to compare whether IOS variables relate to spirometry variables. DESIGN: Spirometry and IOS were performed at baseline and for 20 min after challenge at 5-min intervals. SETTING: Two 6-min exercise challenges, inhaling either room temperature (22.0 degrees C) or cold temperature (- 1 degrees C) dry medical-grade bottled air. At least 48 h was observed between these randomly assigned challenges. PARTICIPANTS: Twenty-two physically active individuals (12 women and 10 men) with probable EIB. INTERVENTIONS: Subjects performed 6 min of stationary cycle ergometry while breathing either cold or room temperature medical-grade dry bottled air. Subjects were instructed to exercise at the highest intensity sustainable for the duration of the challenge. Heart rate and kilojoules of work performed were documented to verify exercise intensity. MEASUREMENTS AND RESULTS: Strong correlations were observed within testing modalities for post-room temperature and post-cold temperature exercise spirometry and IOS values. Spirometry revealed no differences in postexercise peak falls in lung function between conditions; however, IOS identified significant differences in respiratory resistance (p < 0.05), with room temperature-inspired air being more potent than cold temperature-inspired air. CONCLUSIONS: Correlations were found between spirometric and IOS measures of change in airway function for both exercise challenges, indicating close equivalency of the methods. The challenges appeared to elicit the EIB response by a similar mechanism of water loss, and cold temperature did not have an additive effect. IOS detected a difference in degree of response between the temperatures, whereas spirometry indicated no difference, suggesting that IOS is a more sensitive measure of change in airway function.
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Broncoconstricción/fisiología , Ejercicio Físico/fisiología , Adulto , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Microclima , Oscilometría , Espirometría/métodos , TemperaturaRESUMEN
PURPOSE: Reactive oxygen/nitrogen species (ROS/RNS) in resident airway cells may be important in bronchoconstriction following exercise. Glutathione (GSH) is a major lung antioxidant and could influence pathological outcomes in individuals with exercise-induced bronchoconstriction (EIB). This study examined the effects of supplementation with undenatured whey protein (UWP) in subjects exhibiting airway narrowing following eucapnic voluntary hyperventilation (EVH), a surrogate challenge for diagnosis of EIB. UWP is a cysteine donor that augments GSH production. METHODS: In a randomized, double-blind, placebo-controlled study, 18 EIB-positive subjects (age: 25.2 +/- 9.01 yr; weight: 77.3 +/- 18.92 kg; height: 1.7 +/- 0.09 m) with post-EVH falls of > or =10% in FEV1 received 30 g UWP (TX) or casein placebo (PL)/d. Subjects performed 6-min EVH challenges before and after 4 and 8 wk of supplementation. Exhaled nitric oxide (eNO) was measured serially before spirometry and at 1-wk intervals. Spirometry was performed pre- and 5, 10, and 15 min postchallenge. RESULTS: Subjects exhibited significant mean improvement in postchallenge falls in FEV(1) from 0 wk (-22.6 +/- 12.22%) with TX at 4 (-18.9 +/- 12.89%, P < 0.05) and 8 wk (-16.98 +/- 11.61%, P < 0.05) and significant mean reduction in post-EVH peak falls in FEF(25-75) from 0 wk (-40.6 +/- 15.28%) with TX at 4 (-33.1 +/- 17.11%, P < 0.01) and 8 (-29.7 +/- 17.42%, P < 0.05) wk. No changes in FEV(1) or FEF(25-75) were observed in the PL group at any time point. Mean eNO for PL and TX groups at 0, 4, and 8 wk (46.8 +/- 31.33, 46.5 +/- 35.73, 49.3 +/- 37.12 vs 35.2 +/- 26.87, 29.1 +/- 17.26, 34.7 +/- 21.11 ppb, respectively) was not significantly different. CONCLUSIONS: UWP may augment pulmonary antioxidant capacity and be therapeutically beneficial in individuals exhibiting EIB, as postchallenge pulmonary function improved with supplementation. The lack of significant change in eNO suggests that the pulmonary function improvements from UWP supplementation are independent of eNO.
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Asma Inducida por Ejercicio/dietoterapia , Cisteína/administración & dosificación , Suplementos Dietéticos , Proteínas de la Leche/administración & dosificación , Administración Oral , Adulto , Antioxidantes/metabolismo , Asma Inducida por Ejercicio/metabolismo , Asma Inducida por Ejercicio/fisiopatología , Pruebas Respiratorias , Método Doble Ciego , Femenino , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Pruebas de Función Respiratoria , Resultado del Tratamiento , Proteína de Suero de LecheRESUMEN
INTRODUCTION: Exercise-induced bronchoconstriction (EIB) is thought to result from osmotic and thermal events of air conditioning during exercise at high ventilation rates. The purpose of this study was to evaluate lung function after exercise and eucapnic voluntary hyperventilation (EVH) while breathing both room-temperature and cold-temperature dry bottled air. METHODS: Twenty-two subjects were identified as EIB probable by a fall of >or=7% in forced expiratory volume in the first second of exhalation (FEV1) using a 6-min room-temperature EVH challenge (RTEVH; 22.0 degrees C). Subjects then randomly performed three 6-min challenges: cold-temperature EVH (CTEVH; -1 degrees C), room-temperature exercise (RTEX; 22.0 degrees C), and cold-temperature exercise (CTEX; -1 degrees C), with a period of at least 48 h observed between challenges. Spirometry was performed at baseline and at 5, 10, 15, and 20 min postchallenge. RESULTS: Reasonable agreement was found between challenge modes and room-temperature and cold-temperature challenges. Postchallenge percent falls in FEV1 were -15.21, -13.80, -13.12, and -10.69 for RTEVH, CTEVH, RTEX, and CTEX, respectively. RTEVH resulted in a significantly greater percent fall in FEV1 than CTEX (P=0.048); no other differences in FEV1 were observed. CONCLUSION: Similar postchallenge percent falls in FEV1 for room- and cold-temperature EVH and exercise suggest that dryness is essential to test conditions, as cold temperature did not have an additive effect to the EIB response.
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Asma Inducida por Ejercicio/fisiopatología , Frío/efectos adversos , Hiperventilación/fisiopatología , Adulto , Análisis de Varianza , Ejercicio Físico/fisiología , Prueba de Esfuerzo , Femenino , Humanos , Masculino , EspirometríaRESUMEN
BACKGROUND: The efficacy of impulse oscillometry (IOS) to measure airway calibre change is not fully established. OBJECTIVES: To evaluate lung function change after eucapnic voluntary hyperventilation (EVH), and to compare IOS indices with spirometric maximal expiratory flow measurements. METHODS: Twenty subjects (10 airway hyperresponsive [AHR+] and 10 normal [AHR--]) underwent IOS and spirometry before and for 15 min after 6 min EVH (inhaling 5% CO2, 21% O2, balance N2) at a target ventilation of 30 times the baseline value of the forced expiratory volume in 1 s (FEV1) at 20 degrees C. AHR+ was defined by a fall in FEV1 of 10% or greater from baseline after a provoking challenge. Airway resistance at 5 Hz (R5), reactance at 5 Hz, resonant frequency (Fres), area of reactance integrated from 5 Hz to Fres (AX), and FEV1 were determined. RESULTS: No baseline spirometry values correlated with falls in FEV1. Baseline R5 and AX values correlated with peak falls in FEV1 (r= -0.51 and -0.46, respectively; P< 0.05). AHR+ subjects demonstrated greater per cent peak falls in FEV1 than did AHR- subjects following EVH (30.6 +/- 14.0% versus 7.5 +/- 2.6%, respectively; P<0.05). Changes in R5, Fres, reactance and AX were greater for AHR+ subjects than for AHR- subjects and correlated with a fall in FEV1 (r= -0.74, -0.70, 0.69 and -0.73, respectively; P<0.05). At a designated specificity of 80%, the per cent change in R5 (50% or greater) and post-EVH AX (12 cm H2O/L or greater) yielded sensitivities to a 10% fall in FEV1 of 90%. CONCLUSION: IOS is an acceptable measure to determine AHR and can supplement spirometry in lung function evaluation.
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Hiperventilación/fisiopatología , Pruebas de Función Respiratoria/métodos , Adulto , Resistencia de las Vías Respiratorias , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Oscilometría , EspirometríaRESUMEN
PURPOSE: Exercise-induced bronchoconstriction (EIB) is high among ice rink athletes and may be related to exercise ventilation of rink air pollutants. Impaired postchallenge expiratory flows are common for this population; however, baseline lung function and symptoms have not been fully evaluated. METHODS: We examined resting lung function and asthma-like symptoms in relation to airway hyperresponsiveness in National Team female ice hockey players (N = 43). Subjects were grouped according to observed symptoms and medical history as symptomatic ('S') or asymptomatic ('A'). Baseline and postexercise lung function was determined. RESULTS: Seventeen (39.5%) presented symptoms and 9 (21%) had EIB. Baseline FEV1, FEV1/FVC, and FEF25-75 were different between 'S' and 'A' (102 +/- 14% vs 116 +/- 12%, 77.7 +/- 7.5 vs 88.2 +/- 4.5, and 74 +/- 22% vs 118 +/- 24%, respectively; P < 0.05); FVC and PEF were not different. Ten 'S' athletes had <80% FEV1/FVC; 9 had <70% predicted FEF25-75. Six of 9 EIB+ subjects had symptoms; cough occurred in all six and was related to EIB (chi 2 = 4.23, OR = 6.5, CI = 1.1-44.1; P = 0.039). CONCLUSION: Baseline lung function is related to symptoms and precludes EIB in some rink athletes, suggesting that EIB and its development is a heterogeneous and may involve fibrotic as well as inflammatory processes. Small airway dysfunction in ice arena athletes is likely related to internal combustion pollutants emitted from ice resurfacing machines.
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Asma Inducida por Ejercicio/fisiopatología , Hockey , Adulto , Femenino , Humanos , Pruebas de Función RespiratoriaRESUMEN
PURPOSE: To examine the effects of a single 10-mg dose of ML on physical performance in EIB- and EIB+ athletes. METHODS: Twenty-four male college ice hockey players performed two 6-min maximal work accumulation bouts on an electronically braked cycle ergometer in subfreezing conditions (-2.5 +/- 0.4 degrees C) 6-8 h after either ML or placebo (PL) to obtain total work accumulated (kJ); subjects were evaluated for EIB after each exercise trial. RESULTS: Eight (33%) subjects were identified as EIB+ (23.5 +/- 13.35% fall in FEV1); 16 were EIB- (1.8 +/- 3.03% fall in FEV1). ML provided an approximately 50% protection against postexercise fall in FEV1. No significant differences in kJ were found between PL and ML trials for pooled subjects (95.3 +/- 13.69 and 94.8 +/- 13.27 kJ, respectively), EIB- subjects (99.6 +/- 13.26 and 99.0 +/- 11.81 kJ, respectively), or EIB+ subjects (86.8 +/- 10.67 and 86.5 +/- 12.72 kJ, respectively). Total work accumulated for EIB- subjects was significantly greater than for EIB+ subjects for both PL and ML (P < 0.05). CONCLUSION: A single 10-mg dose of ML had no ergogenic effect for EIB- and EIB+ subjects performing short-duration high-intensity exercise in subfreezing temperature, supporting the use of ML as EIB prophylaxis during international sport competition.
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Acetatos/farmacología , Antiasmáticos/farmacología , Frío , Prueba de Esfuerzo , Ejercicio Físico/fisiología , Quinolinas/farmacología , Adulto , Estudios Cruzados , Ciclopropanos , Método Doble Ciego , Hockey/fisiología , Humanos , Pulmón/efectos de los fármacos , Masculino , Pruebas de Función Respiratoria , Sulfuros , Análisis y Desempeño de TareasRESUMEN
Airway responses were compared following 6-minute eucapnic voluntary hyperventilation and 6-minute exercise challenges by examining resting and post-challenge impulse oscillometry and spirometry variables. Twenty-two physically active individuals with probable exercise-induced bronchoconstriction took part in this study. Impulse oscillometry and spirometry were performed at baseline and for 20 minutes post-challenge at 5-minute intervals. High correlation was found between the two measures of change in airway function for both methods of challenge. Impulse oscillometry detected a difference in degree of response to the challenges, whereas spirometry indicated no difference, suggesting that impulse oscillometry is a more sensitive measure of change in airway function.
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Asma Inducida por Ejercicio/fisiopatología , Broncoconstricción/fisiología , Ejercicio Físico/fisiología , Hiperventilación/fisiopatología , Ventilación Pulmonar/fisiología , Adolescente , Adulto , Resistencia de las Vías Respiratorias/fisiología , Área Bajo la Curva , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Hiperventilación/inducido químicamente , Masculino , Flujo Espiratorio Medio Máximo/fisiología , Oscilometría , Espirometría , Capacidad Vital/fisiologíaRESUMEN
Airborne ultrafine and fine particulate matter (PM1 from fossil-fueled internal combustion engines may cause abnormal airway narrowing. Because of high PM1 exposure from ice resurfacing machines, the ice-rink athlete is especially vulnerable to PM1 toxicity. The purpose of this study was to evaluate protection by a single dose of montelukast in college ice hockey players following PM1 exposure exercise. Nine male ice hockey players (age 19.3+/-1.22 yr) performed 4 randomized, double-blinded, high-intensity, 6-min cycle ergometer trials in low [PM1] (2260+/-500 particles/cm3) and high [PM1] (348,600+/-121,600 particles/cm3) after placebo or montelukast. Pre- and postspirometry showed similar peak FEV1 (forced expiratory volume in 1 s) falls between placebo and montelukast after low [PM1] trials (14.5+/-18.06 vs. 9.5+/-11.75% of baseline, respectively). Peak FEV1 falls after high [PM1] trials were greater for placebo than for montelukast (17.3+/-9.79% vs. 1.7+/-5.77% of baseline; p<.0001). High [PM1] FEV1 fall after exercise following montelukast ingestion was less than after exercise following placebo ingestion under high and low [PM1] conditions and after exercise following montelukast ingestion under low [PM1] conditions at 5, 10, and 15 min postchallenge (p<.004, .0006, .009, respectively). Montelukast provided greater protection against bronchoconstriction after exercise during high [PM1] than low [PM1] exposure (approximately 90% vs. approximately 35%), suggesting that bronchoconstriction from PM1 exposure is predominately leukotriene mediated. The precise mechanism of airborne PM1-induced leukotriene-mediated airway narrowing remains unclear.