Miguel Ángel Martínez García

Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis.

Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exercise intolerance. PFKM deficiency is considered as a skeletal muscle glycogenosis, but the relative contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. To elucidate this issue, we have generated mice deficient for PFKM (Pfkm−/−). Here, we show that Pfkm−/− mice had high lethality around weaning and reduced lifespan, because of the metabolic alterations. In skeletal muscle, including respiratory muscles, the lack of PFK activity blocked glycolysis and resulted in considerable glycogen storage and low ATP content. Although erythrocytes of Pfkm−/− mice preserved 50% of PFK activity, they showed strong reduction of 2,3-biphosphoglycerate concentrations and hemolysis, which was associated with compensatory reticulocytosis and splenomegaly. As a consequence of these haematological alterations, and of reduced PFK activity in the heart, Pfkm−/− mice developed cardiac hypertrophy with age. Taken together, these alterations resulted in muscle hypoxia and hypervascularization, impaired oxidative metabolism, fiber necrosis, and exercise intolerance. These results indicate that, in GSDVII, marked alterations in muscle bioenergetics and erythrocyte metabolism interact to produce a complex systemic disorder. Therefore, GSDVII is not simply a muscle glycogenosis, and Pfkm−/− mice constitute a unique model of GSDVII which may be useful for the design and assessment of new therapies.

Eficacia del midazolam para la sedación en la broncoscopia flexible. Un estudio aleatorizado

INTRODUCTION Flexible bronchoscopy (FB) is a procedure which is not usually tolerated well by the patient. This makes the examination more difficult, often needing repetition with the subsequent lowering of diagnostic performance. OBJECTIVE The principal aim of our study is to analyse whether the use of a local anaesthetic with midazolam whilst performing an FB improves the quality of examination in terms of patient tolerance. Also of interest was to find out if this would improve the acceptance of a second or further FB, and the satisfaction of the bronchoscopist in performing these examinations. PATIENTS AND METHODS A randomised, double blind and controlled with placebo, prospective study has been carried out to assess the use of midazolam. This included 152 patients, randomised into two groups: Group A-79 (51.9%) patients who received midazolam before the FB, and Group B-73 (49.1%) patients who received placebo. The patients were given a questionnaire about different aspects of perception of the procedure after the respiratory endoscopy and another was given to the bronchoscopist. RESULTS Both groups started off with a similar assessment of fear and nervousness. Group A gave a much higher score than Group B referring to variables related to symptoms and feeling. Patient cooperation assessed by the bronchoscopist was similar in both groups, although the length of the procedure and difficulty was higher in group B. CONCLUSION Our results show that patients sedated with midazolam tolerate FB better, remember less of the procedure itself and have a better predisposition to repeat the procedure. The bronchoscopist has less difficulties during the procedure and shortens the time using the same techniques during the bronchoscopy. The lack of severe complications and these results suggest the use of sedation with midazolam as routine during FB.

Factores pronósticos en la EPOC

Prolongar la supervivencia de los pacientes con enfermedad pulmonar obstructiva cronica (EPOC) es, y ha sido durante decadas, un objetivo complicado. Sin embargo, poco a poco esta percepcion empieza a cambiar. De la mano de un mejor conocimiento etiopatogenico de la enfermedad, del analisis de las causas de muerte y sobre todo de la identificacion de diversos factores pronosticos, se van dando pasos firmes que permiten afrontar el futuro con mayor optimismo. La presente revision pretende analizar de forma pormenorizada los principales determinantes pronosticos que se han descrito en la literatura medica y valorar sus posibles implicaciones terapeuticas. Tradicionalmente se ha aceptado que el volumen espiratorio forzado en el primer segundo y su descenso acelerado a lo largo del tiempo era uno de los mejores predictores de mortalidad. Este hecho condiciono durante decadas el objetivo terapeutico en la EPOC. Sin embargo, hoy sabemos que la EPOC es una enfermedad con multiples dimensiones, algunas de las cuales tienen importantes consecuencias pronosticas. La hiperinsuflacion pulmonar, la tolerancia al esfuerzo, las exacerbaciones, la co-morbilidad y las manifestaciones sistemicas, especialmente las resultantes de la esfera cardiovascular, son dimensiones que en los ultimos anos se han revelado como potentes predictores de muerte. El sustrato inflamatorio, tanto local como sistemico, parece estar detras de muchas de estas manifestaciones y por ello merece especial consideracion. Estos nuevos factores pronosticos tienen la virtud de ser potencialmente modificables, lo que subraya la necesidad de planificar intervenciones terapeuticas orientadas a revertir sus efectos cambiando de alguna forma la estrategia tradicional.

EPOC y bronquiectasias

Resumen La enfermedad pulmonar obstructiva cronica (EPOC) y las bronquiectasias son 2 de las enfermedades mas frecuentes e infradiagnosticadas de la via aerea. La relacion existente entre ambas puede establecerse desde diferentes puntos de vista. Por una parte, su elevada prevalencia hace que no sea infrecuente observarlas de forma sincronica en un mismo paciente. Por otra parte, estudios recientes han observado una asociacion entre ambas, dado que mas del 50% de los pacientes con EPOC moderada-grave presentan bronquiectasias no explicables por otras causas con la suficiente entidad como para provocar un exceso de inflamacion bronquial y un aumento en el numero de agudizaciones en estos pacientes, posiblemente mediado por un incremento en la colonizacion-infeccion bronquial por microorganismos potencialmente patogenos. Por ultimo, y aunque hasta el momento no se ha demostrado, algunas hipotesis fisiopatologicas indican una relacion de causalidad entre ambas enfermedades en la que la EPOC, especialmente las formas graves, seria un factor de riesgo para la formacion de bronquiectasias.Chronic obstructive pulmonary disease (COPD) and bronchiectasias are two of the most frequent and underdiagnosed diseases of the airways. The association between these two entities can be established from different points of view. On the one hand, because of their high prevalence, the co-occurrence of COPD and bronchiectasias in the same patient is not unusual. On the other hand, recent studies have observed an association between COPD and bronchiectasias, given that more than 50% of patients with moderate-severe COPD show bronchiectasias unexplained by other causes that could provoke an excess of bronchial inflammation, as well as a higher number of exacerbations, possibly mediated by an increase in bronchial colonization-infection by potentially pathogenic microorganisms. Lastly, some physiopathologic hypotheses that remain to be demonstrated suggest a causal relation between the two diseases in which COPD, especially severe forms, would constitute a risk factor for the formation of bronchiectasias.

A Randomised Study of Midazolam for Sedation in Flexible Bronchoscopy

Abstract Introduction Flexible bronchoscopy (FB) is a procedure which is not usually tolerated well by the patient. This makes the examination more difficult, often needing repetition with the subsequent lowering of diagnostic performance. Objective The principal aim of our study is to analyse whether the use of a local anaesthetic with midazolam whilst performing an FB improves the quality of examination in terms of patient tolerance. Also of interest was to find out if this would improve the acceptance of a second or further FB, and the satisfaction of the bronchoscopist in performing these examinations. Patients and methods A randomised, double blind and controlled with placebo, prospective study has been carried out to assess the use of midazolam. This included 152 patients, randomised into two groups: Group A—79 (51.9%) patients who received midazolam before the FB, and Group B—73 (49.1%) patients who received placebo. The patients were given a questionnaire about different aspects of perception of the procedure after the respiratory endoscopy and another was given to the bronchoscopist. Results Both groups started off with a similar assessment of fear and nervousness. Group A gave a much higher score than Group B referring to variables related to symptoms and feeling. Patient cooperation assessed by the bronchoscopist was similar in both groups, although the length of the procedure and difficulty was higher in group B. Conclusion Our results show that patients sedated with midazolam tolerate FB better, remember less of the procedure itself and have a better predisposition to repeat the procedure. The bronchoscopist has less difficulties during the procedure and shortens the time using the same techniques during the bronchoscopy. The lack of severe complications and these results suggest the use of sedation with midazolam as routine during FB.

Tratamiento de las bronquiectasias no debidas a fibrosis quística

Bronchiectasis is currently growing in importance due to both the increase in the number of diagnoses made as well as the negative impact that its presence has on the baseline disease that generates it. A fundamental aspect in these patients is the colonization and infection of the bronchial mucous by potentially pathogenic microorganisms (PPM), which are the cause in most cases of the start of the chronic inflammatory process that results in the destruction and dilatation of the bronchial tree that is characteristic in these patients. The treatment of the colonization and chronic bronchial infection in these patients should be based on prolonged antibiotic therapy in its different presentations. Lately, the inhaled form is becoming especially prominent due to its high efficacy and limited production of important adverse effects. However, one must not overlook the fact that the management of patients with bronchiectasis should be multidisciplinary and multidimensional. In addition to antibiotic treatment, the collaboration of different medical and surgical specialties is essential for the management of the exacerbations, nutritional aspects, respiratory physiotherapy, muscle rehabilitation, complications, inflammation and bronchial hyperreactivity and the hypersecretion that characterizes these patients.Bronchiectasis is currently growing in importance due to both the increase in the number of diagnoses made as well as the negative impact that its presence has on the baseline disease that generates it. A fundamental aspect in these patients is the colonization and infection of the bronchial mucous by potentially pathogenic microorganisms (PPM), which are the cause in most cases of the start of the chronic inflammatory process that results in the destruction and dilatation of the bronchial tree that is characteristic in these patients. The treatment of the colonization and chronic bronchial infection in these patients should be based on prolonged antibiotic therapy in its different presentations. Lately, the inhaled form is becoming especially prominent due to its high efficacy and limited production of important adverse effects. However, one must not overlook the fact that the management of patients with bronchiectasis should be multidisciplinary and multidimensional. In addition to antibiotic treatment, the collaboration of different medical and surgical specialties is essential for the management of the exacerbations, nutritional aspects, respiratory physiotherapy, muscle rehabilitation, complications, inflammation and bronchial hyperreactivity and the hypersecretion that characterizes these patients.

Comorbilidad cardiovascular en la EPOC

Resumen La presencia de alteraciones cardiovasculares entre los pacientes con enfermedad pulmonar obstructiva cronica (EPOC) supera los limites de la casualidad. El tabaquismo, un factor de riesgo comun a ambas entidades, podria explicar, en parte, la fuerza de la asociacion; sin embargo, hay indicios para suponer que otros determinantes, como la inflamacion sistemica, el estres oxidativo, la hipoxemia, la disfuncion endotelial e incluso el propio envejecimiento, podrian estar tambien implicados. En los pacientes donde coinciden ambas enfermedades, las consecuencias finales son manifiestamente peores. La enfermedad cardiovascular (ECV) contribuye a la hospitalizacion de los pacientes con EPOC y tambien a su mortalidad. Aproximadamente, uno de cada 4 pacientes con EPOC fallece de causa cardiovascular. En sentido contrario, la exacerbacion de la EPOC tambien contribuye a un numero mayor de episodios cardiovasculares, e incluso se ha detectado un incremento de la mortalidad entre los pacientes con ECV que presentan EPOC frente a controles no EPOC. Estos condicionantes subrayan la necesidad de desarrollar una vision integral capaz de identificar de forma temprana al candidato y emplear alternativas terapeuticas adecuadas. Se ha sugerido que los vasodilatadores, estatinas o bloqueadores beta pueden mejorar la morbimortalidad del paciente con EPOC, quiza por maximizar el control en la ECV subyacente. No obstante, tambien se apunta que el potencial antiinflamatorio de las estatinas podria ser de interes. Los corticoides inhalados, e incluso algunos broncodilatadores, tambien pueden disminuir la morbilidad cardiovascular. Estos datos son observacionales y deben enjuiciarse con precaucion. No obstante, son suficientemente provocadores para justificar el enorme interes que suscita la interaccion entre 2 de las enfermedades cronicas mas prevalentes del mundo occidental, la EPOC y la ECV.

Antibióticos inhalados en el tratamiento de las bronquiectasias no debidas a fibrosis quística

Inhaled antibiotics are increasingly used in patients with non-cystic fibrosis (CF) bronchiectasis. Currently, there is no formal indication for the use of this therapy in these patients as inhaled antibiotics are currently only indicated in patients with CF. Therefore, prescription in patients with non-CF bronchiectasis will continue to be based on compassionate use until scientific evidence from ongoing clinical trials becomes available. However, the studies performed to date have shown several positive effects on some key parameters such as a reduction in the number of colonies and the quantity and purulence of sputum, improved quality of life and fewer exacerbations, although this therapy has little impact on accelerated loss of pulmonary function. The percentage of eradication varies, with a low rate of resistance. The clearest use of inhaled antibiotics in patients with non-CF bronchiectasis is probably colonization, especially chronic infection with Pseudomonas aeruginosa. Adverse effects are usually mild and consist of local irritation of the airway, although their frequency is greater than that in patients with CF. Currently, various clinical trials are being carried out that aim to establish the indications for inhaled antibiotic therapy in these patients. Due to its special characteristics (high local concentrations of the drug with scarce systemic adverse effects), inhaled antibiotic therapy will undoubtedly be an excellent future option for the management of bronchiectasis, as well as of many other diseases of the airways.Inhaled antibiotics are increasingly used in patients with non-cystic fibrosis (CF) bronchiectasis. Currently, there is no formal indication for the use of this therapy in these patients as inhaled antibiotics are currently only indicated in patients with CF. Therefore, prescription in patients with non-CF bronchiectasis will continue to be based on compassionate use until scientific evidence from ongoing clinical trials becomes available. However, the studies performed to date have shown several positive effects on some key parameters such as a reduction in the number of colonies and the quantity and purulence of sputum, improved quality of life and fewer exacerbations, although this therapy has little impact on accelerated loss of pulmonary function. The percentage of eradication varies, with a low rate of resistance. The clearest use of inhaled antibiotics in patients with non-CF bronchiectasis is probably colonization, especially chronic infection with Pseudomonas aeruginosa. Adverse effects are usually mild and consist of local irritation of the airway, although their frequency is greater than that in patients with CF. Currently, various clinical trials are being carried out that aim to establish the indications for inhaled antibiotic therapy in these patients. Due to its special characteristics (high local concentrations of the drug with scarce systemic adverse effects), inhaled antibiotic therapy will undoubtedly be an excellent future option for the management of bronchiectasis, as well as of many other diseases of the airways.

Tratamiento de las bronquiectasias en el adulto

Bronchiectasis is characterized by the dilation and progressive destruction of the bronchial wall. Its actual importance lies in two points: the increased number of diagnoses due to increased chronic diseases and the use of new diagnostic tools, and its negative impact on quality of life and lung function of patients and the negative prognosis of the causative disease. In practical terms, the treatment of bronchiectasis in adults is based on eight basic pillars: treatment of the etiology if it is known, treatment of the bronchial colonization or infection by potentially pathogenic microorganisms including Pseudomonas aeruginosa (inhaled or systemic antibiotics), treatment of bronchial secretions (chest physiotherapy and mucolytics), treatment of bronchial inflammation (inhaled steroids and macrolides) and hyperresponsiveness (inhaled steroids and bronchodilators), treatment of systemic manifestations (malnutrition), treatment of exacerbations (oral antibiotics, removing secretions and the associated bronchospasm), treatment of complications (hemoptysis, respiratory failure and mucous plugs), and finally, surgical treatment (lung transplantation or resection surgery).

Prognostic Factors in Chronic Obstructive Pulmonary Disease

Efforts over the last few decades to extend the life expectancy of patients with chronic obstructive pulmonary disease (COPD) have faced difficulties, but our perception of the problems involved is now starting to change. Improvements in our understanding of the pathogenic and etiological mechanisms of the disease, analysis of the causes of death, and, in particular, identification of the relevant prognostic factors have resulted in firm advances that allow us to face the future with greater optimism. The aim of this review is to provide a detailed analysis of the chief prognostic factors described in the literature and to evaluate the therapeutic implications of these findings. The traditional view maintained that the accelerated decline over time in forced expiratory volume in 1 second was one of the best predictors of mortality, and this belief has for decades determined the strategies used to treat COPD. However, we now know COPD to be a multidimensional disease and are aware that some of its other manifestations have important prognostic implications. Lung hyperinflation, exercise tolerance, exacerbations, comorbidity, and systemic manifestations—in particular those related to the cardiovascular system—have all been shown in recent years to be strong predictors of mortality. The inflammatory substrate, whether local or systemic, merits special consideration because it appears to be the cause of many of these manifestations. These newly identified prognostic factors are of great interest in that it may be possible to moderate their influence, a circumstance that highlights the need to change the traditional treatment approach and devise therapeutic interventions oriented towards reversing the effects of these factors.