Varenicline in smokers with severe or very severe COPD after 24 weeks of treatment. A descriptive analysis: VALUE study.

A large number of COPD patients are smokers. The particular characteristics of this group as well as their need to quit usually require psychological counselling and pharmacological treatment to achieve abstinence and, often, intensively. Little information is available about this issue.  The main objective of the study was to evaluate the effectiveness of varenicline after 24 weeks of treatment, with continuous abstinence between weeks 9 and 24.  This study was a post-authorization, open label, observational study of prospective follow-up. Patients included were smokers with severe or very severe COPD criteria who were treated with varenicline for 24 weeks, i.e. with a 12-week extension over the usual treatment.  The outcomes in the population of subjects completing 24 weeks of follow-up were at week 24: continuous abstinence 36.8%, 7 days point prevalence abstinence 65.7%, and continuous smoking 31.5%.The outcomes in the intention-to-treat population included at baseline were: continuous abstinence 17.7% of patients, 7 days point prevalence abstinence 31.6%, continuous smoking 15.1% and not valid/unknown 51.8%.  The mean CAT score at week 24 was 15 and reduction from the baseline was 3.77 (paired T test, p<0.01). The most common adverse events reported were nausea, vivid dreams, stomach ache, insomnia, headache and vomiting.  Patients included in VALUE were active smokers despite all of them had a severe COPD which suggests a very high degree of dependence. Although the study do not allow to infer the results to the global population of smokers with severe COPD, the outcomes have shown that, at 24 weeks follow up 36.8% of the patients were successful in quitting but from 79 patients enrolled initially only 17.7% quit.

Differences in cardiovascular risk and health-related quality of life in COPD patients according to clinical phenotype.

Chronic obstructive pulmonary disease (COPD) has a high prevalence and a major impact on health-related quality of life (HRQL). COPD exacerbations are an important cause of morbidity and mortality, affecting cardiovascular risk, and are associated with poorer health status. The aim of this study was to assess the association between cardiovascular risk (CVR) and HRQL, according to exacerbator or non-exacerbator phenotype. We undertook a cross-sectional, observational, descriptive study of 107 patients with COPD. Patients with two or more moderate exacerbations or one severe exacerbation in the previous year were considered as exacerbators. The CVR was calculated with the Framingham scale and SCORE (Systematic Coronary Risk Evaluation) and the HRQL was assessed with the generic questionnaire Short Form-36 Health Survey (SF-36), the St George Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). Statistical analysis was done with SPSS version 26.0 for Windows. The SF-36 and the SGRQ showed lower values for the exacerbator phenotype, indicating a poorer quality of life. The CAT questionnaire showed values above 10 for the exacerbator phenotype, and lower values in the non-exacerbator group. After categorizing the sample according to their median age (65 years), we found a greater deterioration in HRQL in patients under 65 years of age according to the SF-36, the SGRQ and the CAT. We also detected differences in HRQL between non-exacerbator patients with a high CVR according to the Framingham (≥ 20%) and SCORE (≥ 5%) scales compared to those without this risk. A tendency towards worse HRQL was observed in non-exacerbator patients with a high CVR, which was statistically significant for the SGRQ impact domain on the SCORE scale. The CAT also showed a worse quality of life in non-exacerbator patients with a high CVR, which was significant in the Framingham model (Framingham high risk 8.41 vs non-high risk 6.05, p < 0.01). These differences were not observed in exacerbator patients. Our findings confirm that a high CVR influences HRQL in patients with COPD, especially in non-exacerbator patients with a high CVR, measured according to the SGRQ and the CAT.

Effectiveness of a respiratory rehabilitation programme in patients with chronic obstructive pulmonary disease. / Efectividad de un programa de rehabilitación respiratoria en pacientes con enfermedad pulmonar obstructiva crónica.

OBJECTIVE: To evaluate the effectiveness of the multidisciplinary respiratory rehabilitation (RR) programme in patients with severe or very severe chronic obstructive pulmonary disease pre the RR programme, at the end of the programme and one year after the RR, measuring changes in ability to exercise (walking test), effort tolerance(forced expiratory volume (FEV1)) and health-related quality of life. METHOD: Quasi-experimental single group design. We included patients diagnosed with severe or very severe chronic obstructive pulmonary disease (stages III and IV of the GOLD classification) who entered the rehabilitation programme for the years 2011 and 2012. Demographic data, questionnaires on general health-related quality of life (SF-36) and specific to respiratory patients (St George's Respiratory Questionnaire), FEV1% and exercise capacity test (running test 6minutes) were collected. Data were collected before the RR programme, at the end of the RR programme and a year after completing the program. RESULTS: No significant differences in FEV1% values were observed. Regarding exercise capacity, an increase in distance walked in the walking test was noted, which changed significantly after training, 377±59.7 to 415±79 m after one year (P<.01). A statistically significant improvement in mean scores of HRQoL was observed, except for the emotional role dimension of the SF-36 questionnaire. CONCLUSION: A pulmonary rehabilitation programme for 8 weeks improved the exercise capacity, dyspnoea and quality of life of patients with severe and very severe chronic obstructive pulmonary disease.

Short-fiber protein of ad40 confers enteric tropism and protection against acidic gastrointestinal conditions.

The lack of vectors for selective gene delivery to the intestine has hampered the development of gene therapy strategies for intestinal diseases. We hypothesized that chimeric adenoviruses of Ad5 (species C) displaying proteins of the naturally enteric Ad40 (species F) might hold the intestinal tropism of the species F and thus be useful for gene delivery to the intestine. As oral-fecal dissemination of enteric adenovirus must withstand the conditions encountered in the gastrointestinal tract, we studied the resistance of chimeric Ad5 carrying the short-fiber protein of Ad40 to acid milieu and proteases and found that the Ad40 short fiber confers resistance to inactivation in acidic conditions and that AdF/40S was further activated upon exposure to low pH. In contrast, the chimeric AdF/40S exhibited only a slightly higher protease resistance compared with Ad5 to proteases present in simulated gastric juice. Then, the biodistribution of different chimeric adenoviruses by oral, rectal, and intravenous routes was tested. Expression of reporter ß-galactosidase was measured in extracts of 15 different organs 3 days after administration. Our results indicate that among the chimeric viruses, only intrarectally given AdF/40S infected the colon (preferentially enteroendocrine cells and macrophages) and to a lesser extent, the small intestine, whereas Ad5 infectivity was very poor in all tissues. Additional in vitro experiments showed improved infectivity of AdF/40S also in different human epithelial cell lines. Therefore, our results point at the chimeric adenovirus AdF/40S as an interesting vector for selective gene delivery to treat intestinal diseases.

Efectividad de un programa de rehabilitación respiratoria en pacientes con enfermedad pulmonar obstructiva crónica / Effectiveness of a respiratory rehabilitation programme in patients with chronic obstructive pulmonary disease

Objetivo: Evaluar la efectividad de un programa de rehabilitación respiratoria (RR) multidisciplinar en pacientes con enfermedad pulmonar obstructiva crónica grave o muy grave preprograma RR, al terminar el programa y al año de haber realizado la RR midiendo los cambios producidos en: la capacidad de ejercicio (test de marcha), mejoría en la tolerancia al esfuerzo (volumen espiratorio forzado [FEV1]) y en la calidad de vida relacionada con la salud. Método: Diseño cuasi experimental con un solo grupo. Se incluyeron a pacientes con diagnóstico de enfermedad pulmonar obstructiva crónica grave o muy grave (estadios III y IV de la clasificación GOLD) que entraron en el programa de RR entre 2011 y 2012. Se recogieron datos demográficos, calidad de vida relacionada con la salud general (SF-36) y específica para enfermos respiratorios (Cuestionario Respiratorio St. George), FEV1% y test de capacidad de ejercicio (prueba de la marcha de 6min). La recogida de datos se realizó preprograma RR, al terminar el programa de RR y al año de haber acabado el programa. Resultados: No se observaron diferencias significativas en los valores de FEV1%. Respecto a la capacidad de ejercicio se observó un aumento de la distancia recorrida en el test de marcha, que se modificó significativamente después del entrenamiento, de 377±59,7 a 415±79m al año (p<0,01). Se observó una mejoría estadísticamente significativa en las 3 dimensiones del Cuestionario Respiratorio St. George. Las medias de las puntuaciones obtenidas de la calidad de vida relacionada con la salud mejoraron significativamente en todas las dimensiones excepto en la dimensión rol emocional del cuestionario SF-36. Conclusión Un programa de RR de 8 semanas de duración mejora la capacidad de realizar ejercicio, la disnea y la calidad de vida en pacientes con enfermedad pulmonar obstructiva crónica grave y muy grave (AU)

Objective: To evaluate the effectiveness of the multidisciplinary respiratory rehabilitation (RR) programme in patients with severe or very severe chronic obstructive pulmonary disease pre the RR programme, at the end of the programme and one year after the RR, measuring changes in ability to exercise (walking test), effort tolerance(forced expiratory volume (FEV1)) and health-related quality of life. Method: Quasi-experimental single group design. We included patients diagnosed with severe or very severe chronic obstructive pulmonary disease (stages III and IV of the GOLD classification) who entered the rehabilitation programme for the years 2011 and 2012. Demographic data, questionnaires on general health-related quality of life (SF-36) and specific to respiratory patients (St George's Respiratory Questionnaire), FEV1% and exercise capacity test (running test 6minutes) were collected. Data were collected before the RR programme, at the end of the RR programme and a year after completing the program. Results: No significant differences in FEV1% values were observed. Regarding exercise capacity, an increase in distance walked in the walking test was noted, which changed significantly after training, 377±59.7 to 415±79 m after one year (P<.01). A statistically significant improvement in mean scores of HRQoL was observed, except for the emotional role dimension of the SF-36 questionnaire. Conclusion: A pulmonary rehabilitation programme for 8 weeks improved the exercise capacity, dyspnoea and quality of life of patients with severe and very severe chronic obstructive pulmonary disease (AU)

The direct activation of MIK, a germinal center kinase (GCK)-like kinase, by MARK, a maize atypical receptor kinase, suggests a new mechanism for signaling through kinase-dead receptors.

Signaling by receptor protein kinases (RPKs) involves their dimerization and transphosphorylation. However, atypical RPKs with kinase-defective domains have been described recently. Some of them are essential for proper signaling in animal systems, although the precise mechanism involved is unknown in most cases. Here we describe the cloning and characterization of an atypical plant receptor kinase from maize, MARK, which does not phosphorylate in vitro. A yeast two-hybrid approach has allowed us to identify a new germinal center kinase (GCK)-related protein, MIK, that interacts with MARK. Interestingly, the interaction of the intracellular domain of MARK with the regulator domain of MIK strongly induces MIK kinase activity. As some GCK-related proteins connect cell-surface receptors to the intracellular MAPK cascades, the activation of MIK by direct interaction with MARK could illustrate a new mechanism for signaling through atypical RPKs.