RESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) and sleep apnea are common conditions and often coexist. The proper diagnosis of sleep apnea may affect the management and outcome of patients with COPD. OBJECTIVE: To determine the accuracy of home nocturnal oximetry to distinguish between nocturnal oxygen desaturation related to COPD alone or to sleep apnea in patients with moderate-to-severe COPD who have significant nocturnal hypoxemia with cyclical changes in saturation. METHODS: This study involved a comparison of home nocturnal oximetry and laboratory-based polysomnography (PSG) in patients with moderate-to-severe COPD considered for inclusion in a trial of nocturnal oxygen therapy. All of the patients had significant nocturnal oxygen desaturation (defined as ≥30% of the recording time with a transcutaneous arterial oxygen saturation <90%) with cyclical changes in saturation suggestive of sleep apnea. RESULTS: PSG was obtained in 90 patients; 45 patients (mean age = 68 years, SD = 8; 71% men; mean forced expiratory volume in 1 s [FEV1] = 50.6% predicted value, SD = 18.6%; data from 41 patients) fulfilled the criteria for sleep apnea (mean apnea-hypopnea index = 32.6 events/h, SD = 19.9) and 45 patients (mean age = 69 years, SD = 8; 87% men; mean FEV1 predicted value 44.6%, SD = 15%) did not (mean apnea-hypopnea index = 5.5 events/h, SD = 3.8). None of the patients' characteristics (including demographic, anthropometric, and physiologic measures) predicted the diagnosis of sleep apnea according to PSG results. CONCLUSION: The diagnosis of sleep apnea in patients with moderate to severe COPD cannot rely on nocturnal oximetry alone, even when typical cyclical changes in saturation are seen on oximetry tracing. When suspecting an overlap syndrome, a full-night, in-laboratory PSG should be obtained.
Asunto(s)
Hipoxia/metabolismo , Oximetría/métodos , Polisomnografía/métodos , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Apnea Obstructiva del Sueño/diagnóstico , Anciano , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Ambulatorio , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Sueño , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismoRESUMEN
Long-term oxygen therapy (LTOT) has beneficial effects on survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia at rest. Two landmark trials suggested that these benefits depend on the time of exposure to oxygen. Patients are usually prescribed LTOT for at least 15-18 hours/day. The primary objective of this study was to determine the average daily exposure to supplemental oxygen in patients with severely hypoxemic COPD who were newly prescribed LTOT and the proportion of patients who were adherent to their prescription. The secondary objective was to identify predictors of compliance to LTOT. We performed a retrospective observational study of patients newly registered in a regional home oxygen program in Quebec, Canada, between July 1, 2013, and December 31, 2014. Daily exposure to oxygen was objectively measured from the concentrator's counter clock. From 196 patients registered in the program during the study period, 115 contributed to the analysis. Most patients ( n = 84; 73%) were prescribed oxygen for ≥18 hours/day. Overall, the 115 patients were exposed to home oxygen for 17.8 hours/day; 60% of the patients were compliant according to our definition. Increasing age and ambulatory oxygen utilization predicted adherence to oxygen therapy. Adherence to home oxygen therapy is suboptimal. Behavioral and psychological interventions to improve compliance to LTOT should be investigated.
Asunto(s)
Terapia por Inhalación de Oxígeno , Oxígeno/administración & dosificación , Cooperación del Paciente/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipoxia/etiología , Masculino , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Estudios Retrospectivos , Autocuidado , Factores de TiempoRESUMEN
The mechanism by which herpesviruses acquire their tegument is not yet clear. One model is that outer tegument proteins are recruited by the cytoplasmic tails of viral glycoproteins. In the case of herpes simplex virus tegument protein VP22, interactions with the glycoproteins gE and gD have been shown. We have previously shown that the C-terminal half of VP22 contains the necessary signal for assembly into the virus. Here, we show that during infection VP22 interacts with gE and gM, as well as its tegument partner VP16. However, by using a range of techniques we were unable to demonstrate VP22 binding to gD. By using pulldown assays, we show that while the cytoplasmic tails of both gE and gM interact with VP22, only gE interacts efficiently with the C-terminal packaging domain of VP22. Furthermore, gE but not gM can recruit VP22 to the Golgi/trans-Golgi network region of the cell in the absence of other virus proteins. To examine the role of the gE-VP22 interaction in infection, we constructed a recombinant virus expressing a mutant VP22 protein with a 14-residue deletion that is unable to bind gE (Delta gEbind). Coimmunoprecipitation assays confirmed that this variant of VP22 was unable to complex with gE. Moreover, VP22 was no longer recruited to its characteristic cytoplasmic trafficking complexes but exhibited a diffuse localization. Importantly, packaging of this variant into virions was abrogated. The mutant virus exhibited poor growth in epithelial cells, similar to the defect we have observed for a VP22 knockout virus. These results suggest that deletion of just 14 residues from the VP22 protein is sufficient to inhibit binding to gE and hence recruitment to the viral envelope and assembly into the virus, resulting in a growth phenotype equivalent to that produced by deleting the entire reading frame.
Asunto(s)
Herpesvirus Humano 1/fisiología , Proteínas del Envoltorio Viral/metabolismo , Proteínas Estructurales Virales/metabolismo , Virión/fisiología , Animales , Células COS , Chlorocebus aethiops , Herpesvirus Humano 1/metabolismo , Eliminación de Secuencia , Células Vero , Virión/metabolismo , Ensamble de Virus , Red trans-Golgi/metabolismo , Red trans-Golgi/virologíaRESUMEN
BACKGROUND: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. METHODS: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. RESULTS: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61). CONCLUSION: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation.The reviews of this paper are available via the supplemental material section.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Broncodilatadores/uso terapéutico , Disnea/tratamiento farmacológico , Glicopirrolato/análogos & derivados , Indanos/uso terapéutico , Pulmón/efectos de los fármacos , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/uso terapéutico , Bromuro de Tiotropio/uso terapéutico , Prueba de Paso , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Anciano , Broncodilatadores/efectos adversos , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Disnea/diagnóstico , Disnea/fisiopatología , Tolerancia al Ejercicio , Femenino , Glicopirrolato/efectos adversos , Glicopirrolato/uso terapéutico , Humanos , Indanos/efectos adversos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Ontario , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quebec , Quinolonas/efectos adversos , Recuperación de la Función , Factores de Tiempo , Bromuro de Tiotropio/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: Chloramines, which are produced by the reaction of chlorine with the organic matter present in indoor pools, are potential airway irritants in swimmers. The objective of this study was to compare the prevalence of health complaints of young swimmers and young indoor soccer players and to evaluate the relationship between chloramine concentrations and the athletes' health complaints. METHODS: Health complaints were first (Part 1) documented by questionnaire in 305 competitive swimmers and 499 indoor soccer players of the Québec City region (Canada). Then, (Part 2) health complaints were documented during five training sessions in 72 competitive swimmers in comparison to 73 soccer players. The chloramines in the swimming pool air and water were measured as well as the peak expiratory flow (PEF) before and after the training session. RESULTS: In Part 1, the swimmers reported more lower (adjusted OR: 1.5; IC95%= 1.0-2.2) and upper respiratory symptoms (adjusted OR: 3.7; IC95%= 2.4-5.8). In Part 2, the swimmers experienced more frequent lower (adjusted OR: 3.5; IC95%= 2.0-6.0) and upper respiratory symptoms (adjusted OR: 3.1; IC95%= 1.8-5.4). Overall, swimmers exposed to the highest levels of chloramines in the air and water had more respiratory complaints. CONCLUSIONS: Swimmers exposed to chlorination by-products in both the water and air of indoor swimming pools experience frequent respiratory symptoms that could potentially be reduced by limiting exposure to these products.
Asunto(s)
Cloraminas/análisis , Enfermedades Respiratorias/inducido químicamente , Fútbol/fisiología , Piscinas , Natación/fisiología , Adolescente , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Distribución de Chi-Cuadrado , Niño , Cloraminas/toxicidad , Cloro/toxicidad , Femenino , Estado de Salud , Humanos , Masculino , Prevalencia , Quebec/epidemiología , Enfermedades Respiratorias/epidemiología , Fútbol/estadística & datos numéricos , Encuestas y Cuestionarios , Natación/estadística & datos numéricos , Microbiología del Agua , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidadRESUMEN
The role of the herpes simplex virus tegument protein VP22 is not yet known. Here we describe the characterization of a virus in which the entire VP22 open reading frame has been deleted. We show that VP22 is not essential for virus growth but that virus lacking VP22 (Delta22) displays a cell-specific replication defect in epithelial MDBK cells. Virus particles assembled in the absence of VP22 show few obvious differences to wild-type (WT) particles, except for a moderate reduction in glycoproteins gD and gB. In addition, the Delta22 virus exhibits a general delay in the initiation of virus protein synthesis, but this is not due to a glycoprotein-related defect in virus entry. Intriguingly, however, the absence of VP22 has an obvious effect on the intracellular level of the immediate-early (IE) protein ICP0. Moreover, following translocation from the nucleus to the cytoplasm, ICP0 is unable to localize to the characteristic cytoplasmic sites observed in a WT infection. We demonstrate that, in WT-infected cells, VP22 and ICP0 are concentrated in the same cytoplasmic sites. Furthermore, we show that, while ICP0 and ICP4 are components of WT extracellular virions, the altered localization of ICP0 in the cytoplasm of Delta22-infected cells correlates with an absence of both ICP0 and ICP4 from Delta22 virions. Hence, while a role has not yet been defined for virion IE proteins in virus infection, our results suggest that their incorporation is a specific event requiring the tegument protein VP22. This report provides the first direct evidence that VP22 influences virus assembly.
Asunto(s)
Herpesvirus Humano 1/fisiología , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Estructurales Virales/fisiología , Virión/metabolismo , Animales , Bovinos , Línea Celular , Cricetinae , Citoplasma/metabolismo , Eliminación de Gen , Glicoproteínas , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Humanos , Proteínas Estructurales Virales/genética , Ensamble de VirusRESUMEN
Many steps along the herpesvirus assembly and maturation pathway remain unclear. In particular, the acquisition of the virus tegument is a poorly understood process, and the molecular interactions involved in tegument assembly have not yet been defined. Previously we have shown that the two major herpes simplex virus tegument proteins VP22 and VP16 are able to interact, although the relevance of this to virus assembly is not clear. Here we have constructed a number of recombinant viruses expressing N- and C-terminal truncations of VP22 and have used them to identify regions of the protein involved in its assembly into the virus structure. Analysis of the packaging of these VP22 variants into extracellular virions revealed that the C terminus of VP22 is absolutely required for this process, with removal of the C-terminal 89 residues abrogating its incorporation. However, while these 89 residues alone were sufficient for specific incorporation of small amounts of VP22 into the tegument, efficient packaging of VP22 to the levels of full-length protein required an additional 52 residues of the protein. Coimmunoprecipitation assays indicated that these 52 residues also contained the interaction domain for VP16. Furthermore, analysis of the subcellular localization of the mutant forms of VP22 revealed that only those truncations that were efficiently assembled formed characteristic cytoplasmic trafficking complexes, suggesting that these complexes may represent the cellular location for VP22 assembly into the virus. Taken together, these results suggest that there are two determinants involved in the packaging of VP22-a C-terminal domain and an internal VP16 interaction domain, both of which are required for the efficient recruitment of VP22 to sites of virus assembly.
Asunto(s)
Herpesvirus Humano 1/fisiología , Fosfoproteínas/fisiología , Proteínas Estructurales Virales/fisiología , Animales , Línea Celular , Citoplasma/virología , Proteína Vmw65 de Virus del Herpes Simple/metabolismo , Fosfoproteínas/metabolismo , Estructura Terciaria de Proteína/fisiología , Proteínas Estructurales Virales/metabolismo , Ensamble de VirusRESUMEN
A novel caspase-like activity, which is directly regulated with cell proliferation is a candidate to regulate the abundance of the cyclin-dependent kinase inhibitor, p27(KIP1), in human lymphoid cells. This activity, which we term KIPase activity, can also cleave a subset of caspase substrates. Here we demonstrate that KIPase is a novel enzyme distinct from any of the previously characterized human caspases. We show that KIPase is active in a variety of cell lineages, its activity is associated with the proliferation of the human T-cell line, Jurkat, and is not inhibited by the broad spectrum caspase inhibitor z-VAD-fmk. Gel filtration analysis revealed that KIPase has a native molecular mass of approximately 100-200 kDa. Furthermore, the activity of KIPase does not change during apoptosis induced by either ligation of FAS or exposure of cells to etoposide. The uniqueness of KIPase is demonstrated by the fact that none of the human caspases tested (1-10) are able to cleave a specific KIPase substrate (Ac-DPSD-AMC) and that an aldehyde modified derivative of the DPSD tetra peptide is unable to inhibit caspases, but is a good inhibitor of KIPase activity. This supports a hypothesis whereby KIPase is a currently unidentified caspase-like enzyme which regulates the abundance of p27(KIP1) in a proliferation-dependent manner.