Comparison of peak inspiratory flow rate via the Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very severe COPD: a randomized cross-over trial.

BACKGROUND: The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. METHODS: This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. RESULTS: In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. CONCLUSIONS: Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients' COPD severity, age or gender. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.

Is coproporphyrin III a copper-acquisition compound in Paracoccus denitrificans?

Paracoccus denitrificans is a soil bacterium which can respire aerobically and also denitrify if oxygen is absent. Both processes are highly dependent on copper enzymes and copper is therefore likely to be an essential trace element for the bacterium. If copper is not easily available, a copper-acquisition mechanism would be highly beneficial. In this paper, we have addressed the question of whether Paracoccus secretes a copper-acquisition compound functionally analogous to that found in some methanotrophs. Bacteria were grown both in copper-containing and copper-deficient denitrification media, cells were removed by centrifugation and the supernatant was analysed using chromatography and spectroscopy. Bacterial growth yield in the absence of copper was 70-80% of that in the copper-containing medium. A notable difference between the two culture conditions was that spent copper-deficient medium was pigmented, whereas the copper-containing medium was not. Spectrophotometry indicated that a red compound with an absorption maximum at 405 nm was produced under copper-limited conditions. In addition to the strong 405 nm maximum, the visible spectrum of the purified red molecule had weaker maxima at 535 nm and 570 nm, features typical of metallated tetrapyrroles. Mass spectrometry showed that the purified pigment had a molecular mass of 716.18. Moreover, the fine structure of the mass spectrum suggested the presence of zinc and was consistent with the chemical formula of C(36)H(36)N(4)O(8)Zn. The presence of zinc was also demonstrated using inductively coupled plasma atomic emission spectroscopy. Fragmentation analysis with mass spectrometry showed the release of consecutive 59 Da fragments, assignable to four -CH(2)-COOH moieties. Thin layer chromatography as well as NMR analysis of the C-13/N-15 labelled red pigment suggested that it is predominantly zinc coproporphyrin III with a minor fraction of metal-free coproporphyrin III. We propose that in a copper-poor environment P. denitrificans secretes coproporphyrin III for copper chelation and subsequent uptake of the bound copper into the cell. Consistent with this idea, cell yields of copper-deficient cultures grown in the presence of 1 microM copper-coproporphyrin III were 90-95% of the yields of cultures grown in the normal copper-containing media. Coproporphyrin III may work as a copper-acquisition compound in P. denitrificans.

Serum cystatin C: a non-invasive marker of liver fibrosis or of current liver fibrogenesis in chronic hepatitis C? .

BACKGROUND: Serum levels of cystatin C, an endogenous inhibitor of cysteine proteases, provide an alternative method to creatinine-based criteria for measuring glomerular filtration rate. Preliminary data suggested that serum cystatin C levels parallel with the stage of liver fibrosis in chronic liver disorders. Our aim has been to evaluate the possible role of serum cystatin C as a marker of liver fibrosis in hepatitis C virus (HCV)-induced chronic liver disease. MATERIAL AND METHODS: 100 consecutive patients (56 men, mean age 51.2 ± 9.5 yrs) with HCV-induced chronic liver disease, scheduled for their first liver biopsy and naïve for antiviral therapy were included. Liver fibrosis was evaluated with the METAVIR score. Serum cystatin C and standard laboratory tests were measured simultaneously. Patients with ethanol abuse (> 50 g/day), HBV or HIV coinfection or plasma creatinine ≥ 1.20 mg/dL were excluded. In addition, a second group of 16 patients fulfilling the same requisites and diagnosed with HCV-induced compensated cirrhosis by clinical evidence of portal hypertension was included. RESULTS: Serum cystatin C levels significantly increase from F0 to F2 fibrosis stages, remained stable in F3 and F4 stages and increased again in the group of non-biopsied compensated cirrhosis. Serum cystatin C levels were higher in patients with moderate-advanced necroinflammation in the liver biopsy. CONCLUSION: Serum cystatin C level may reflect current fibrogenic and necroinflammatory activities in chronic HCV-induced liver disease with normal renal function but can not be considered as a non-invasive marker of liver fibrosis.

Manejo multimodal de aneurisma cirsoideo. Reporte de un caso y revisión de la literatura / Multimodal Management of Cirsoid Aneurysm. Case Report and Literature Review

Resumen Las malformaciones arteriovenosas AVM del cuero cabelludo, comúnmente conocidas como aneurismas cirsoides, son colecciones complejas de arterias y venas que se comunican directamente. Dependiendo de su tamaño y complejidad, se puede utilizar una variedad de estrategias para tratarlos. Se presenta el caso de un paciente del sexo masculino de 53 años de edad, que acudió a valoración por presentar una aumento de volumen de una lesión pulsátil que se extendía desde la región parietotemporal derecha acompañado de cefalea holocraneana y tinnitus, se realizó una angiotomografía cerebral en la que se observó una lesión compuesta de imágenes serpentiformes ectásicas, con una localización extracraneal derecha, posteriormente se realizó una angiografía cerebral diagnóstica que demostró un cortocircuito arteriovenoso plexiforme y fistuloso frontoparietal derecho alimentado por aferencias provenientes de la arteria temporal superficial, auricular posterior, occipital y meníngea media derechas, con drenaje a través de una vena varicosa y ectásica hacia la vena yugular externa. Se realizó por vía femoral una embolización por vía endovascular del cortocircuito arteriovenoso en dos tiempos, logrando una construcción de "olla a presión" para realizar la inyección de líquido embolizante y tener una embolización subtotal del 93%, con esto se pudo realizar una resección microquirúrgica con un abordaje frontoparietotemporal derecho, resecando la parte más profunda, y dejando la piel cabelluda con vasos embolizados sin resecar. Para el cierre de la herida quirúrgica se realizó rotación de colgajo simple para cubrir el defecto de piel derivado de su resección. Se sometió al paciente a panangiografía cerebral postresección, y se identificó la ausencia de cortocircuito arteriovenoso. Dependiendo de la extensión y la complejidad anatómica de la malformación, las manifestaciones clínicas pueden variar. Más del 80% de las MAV estarán presentes al nacer y el resto se pueden desarrollar después de un trauma craneal o intervenciones quirúrgicas. Se necesita una intervención terapéutica adecuada a través de una angiografía selectiva, durante la cual se puede realizar la embolización endovascular de los principales vasos de alimentación antes de la intervención quirúrgica abierta. Las reconstrucciones por tomografía computarizada tridimensionales por volumen se pueden utilizar para una mayor planificación quirúrgica, la reducción del aporte arterial postembolización disminuirá la hemorragia intraoperatoria, facilitando la resección quirúrgica total. La eliminación puede dar lugar a defectos cutáneos grandes y de espesor completo que pueden ser difíciles de reconstruir sin comprometer los resultados funcionales y cosméticos.

Abstract Scalp arteriovenous malformations AVMs, commonly known as cirsoid aneurysms, are complex collections of arteries and veins that communicate directly. It has been postulated that AVMs occur both through the activation of inactive fistulous lesions and through the formation of new fistulous vascular channels through the canalization of injured vessels. Depending on their size and complexity, a variety of strategies can be used to treat them. The case of a 53-year-old male is presented who came for evaluation due to an increase in the volume of a pulsating lesion that extended from the right parietotemporal region accompanied by holocraneal headache and tinnitus. A cerebral angiotomography was performed in which a lesion composed of ectatic serpentine images, with a right extracranial location, subsequently diagnostic cerebral angiography was performed demonstrating a right frontoparietal fistulous and plexiform arteriovenous shunt fed by afferents from the right superficial temporal, posterior auricular, occipital and middle meningeal arteries, with drainage through a varicose and ectatic vein towards the external jugular vein. An endovascular embolization of the arteriovenous shunt was performed via the femoral route in two stages, achieving a "pressure cooker" construction to perform the injection of embolizing fluid and have a subtotal embolization of 93%, with this it was possible to perform a microsurgical resection with a right fronto-parietal-temporal approach resecting the deepest part, leaving the scalp with embolized vessels without resecting. To close the surgical wound, a simple flap rotation was performed to cover the skin defect derived from its resection. The patient underwent post-resection cerebral panangiography, identifying the absence of arteriovenous shunt. Depending on the extent and anatomical complexity of the malformation, clinical manifestations may vary. More than 80% of AVMs will be present at birth and the rest may develop after head trauma or surgical interventions. Appropriate therapeutic intervention is needed through selective angiography, during which endovascular embolization of the major feeding vessels can be performed before open surgical intervention. Volume-based three-dimensional computed tomography reconstructions can be used for further planning. Surgical reduction of post-embolization arterial supply will reduce intraoperative hemorrhage, facilitating total surgical resection. Removal can result in large, full-thickness skin defects that may be difficult to reconstruct without compromising functional and cosmetic results.

Patient perception of Breezhaler® and Ellipta® device feedback mechanisms in COPD: The ADVANTAGE Study.

OBJECTIVES: The primary objective of the ADVANTAGE study was to compare device-naïve chronic obstructive pulmonary disease (COPD) patients' perception of the Breezhaler® and Ellipta® devices' feedback mechanisms of dose delivery confirmation. The secondary objective was to assess comfort with the inhalers' mouthpiece in terms of ease to form a tight seal around the mouthpiece. These objectives were achieved by using a novel, patient perception of inhaler questionnaire developed and tested during cognitive interviews of patients by Evidera, London, United Kingdom. METHODS: Ten COPD patients were interviewed to collect feedback on the interpretation, relevance and language of the questionnaire. This questionnaire was then used in ADVANTAGE to compare patients' perception (n = 100) of both devices. Patients completed the questionnaire after a single inhalation of placebo through each inhaler. RESULTS: Using the final questionnaire, patients reported being more confident of the feedback mechanism of Breezhaler than that of the Ellipta device (mean score 4.3 versus 3.6 respectively, estimated difference [95% CI]: 0.75 [0.51, 0.99], p < .0001). Patients also reported better comfort (ease to form a tight seal with the lips) with the Breezhaler mouthpiece than the Ellipta mouthpiece (mean score 4.3 versus 3.9 respectively, estimated difference [95% CI]: 0.41 [0.21, 0.61], p < .0001). There were no safety concerns associated with either device. CONCLUSION: COPD patients showed greater preference for the Breezhaler over the Ellipta inhaler for confidence of dose delivery and comfort of the mouthpiece. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov number NCT02551224).

Manejo de las enfermedades intersticiales en Argentina: Una encuesta a neumonólogos / Management of Interstitial Lung Diseases in Argentina: a Survey to Pulmonologists

Introducción: Las enfermedades pulmonares intersticiales difusas (EPID) son un grupo de enfermedades raras que, si bien comparten ciertas características clínicas, tienen un pronóstico muy diferente. La fibrosis pulmonar idiopática (FPI) es la más prevalente en muchos países y su diagnóstico puede ser dificultoso. Luego de los resultados expuestos en el consenso sobre diagnóstico y manejo de la FPI, y la llegada de nuevas drogas como la pirfenidona, se ha modifcado el enfoque de esta enfermedad. Se realizó una encuesta a neumonólogos argentinos, con el fin de evaluar la aceptabilidad e implementación de estas guías en Argentina. Materiales y métodos: Se diseñó una encuesta con 24 preguntas. Entre los datos que se recolectaron en el cuestionario estaban demografía de los encuestados, lugar de trabajo (instituciones públicas, privadas, grandes o pequeños centros o instituciones), frecuencia con la que evaluaban pacientes con FPI, disponibilidad de pruebas diagnósticas y estrategias diagnósticas empleadas para pacientes con EPID. Por último, la encuesta se focalizó en las recomendaciones terapéuticas en los pacientes diagnosticados como FPI. Dicha encuesta fue completada durante el Congreso Argentino de Medicina Respiratoria que se realizó en el 2013 en la ciudad de Mendoza. La misma metodología y cuestionario fueron utilizados previamente en el Congreso Argentino de Medicina Respiratoria del 2011. Resultados: Un total de 252 médicos respondieron la encuesta en el 2013, lo que representó alrededor del 20% de los concurrentes al congreso. El método complementario de mayor disponibilidad fue la prueba de marcha de 6 minutos (PM6M). El método complementario más utilizado fue la tomografía computada de tórax (86.9% de los encuestados la realizaban ante la sospecha de EPID) y solo el 44.4% de los encuestados realizaban difusión de monóxido de carbono (DLCO) en todos sus pacientes. Cerca del 50% de los encuestados consultaban a centros de referencia en menos del 30% de sus casos con sospecha de EPID. Menos del 20% de los respondedores consideraban que llegaban a un diagnóstico defnitivo de EPID en más del 60% de sus pacientes. La distribución final de los diagnósticos fue heterogénea. Notablemente, casi el 50% de los encuestados consideraba que la FPI había sido el diagnóstico final en menos de 30% de sus pacientes. Solo el 30% de los encuestados prescribieron pirfenidona como tratamiento de elección en la FPI y más del 60% todavía continuaban prescribiendo tratamientos que incluían diferentes combinaciones de corticoides e inmunosupresores. Conclusiones: Nuestra encuesta sugiere que existen dificultades en el abordaje diagnóstico de estas entidades, que existe un bajo porcentaje de pacientes que son evaluados en centros de referencia y que hay una baja proporción de estos que reciben tratamiento específico.

Background: Diffuse interstitial (or parenchymal) lung diseases (ILDs) are a very large group of diseases that although they share certain clinical features, have a very different prognosis. Idiopathic pulmonary fibrosis (IPF) is the most prevalent in many countries and its diagnosis can be difficult. After the results shown in the consensus on diagnosis and management of IPF, and the arrival of new drugs such as pirfenidone, the approach to this disease have changed. A survey was performed to argentine pulmonologists in order to evaluate the acceptability and implementation of these guidelines in Argentina. Material and Methods: A survey of 24 questions was designed. Among the data collected in the questionnaire were demographics of respondents, workplace (public or private healthcare facilities, referral center, large or small healthcare centers or institutions), frequency at which IPF patients were examined, availability of diagnostic tests, and diagnostic strategies used with ILD patients. Finally, the survey focused on therapeutic recommendations for patients diagnosed with IPF. The survey was completed during the Argentine Congress of Respiratory Medicine held in 2013 in the city of Mendoza. The same methodology and questionnaire were previously used in the Argentine Congress of Respiratory Medicine in 2011. Results: In 2013, a total of 252 physicians completed the survey, which represented approximately 20% of Congress attendees. The complementary test of higher availability was the the six minutes walk test (6MWT). The most widely used supplementary method was thoracic computed tomography (CT) as 86.9% of the responders used it if they suspected ILD, and only 44.4% of the responders used diffusing capacity of the lungs for carbon monoxide (DLCO) with all their patients. Almost 50% of the responders consulted referral centers for less than 30% of patients with suspected ILD. Less than 20% of the responders considered that they reached a final diagnosis of ILD in over 60% of their patients. Final distribution of diagnosis was heterogeneous. Interestingly, almost 50% of the responders considered IPF as the fnal diagnosis in less than 30% of their patients. Approximately 50% of the responders answered that less than 20% of their IPF patients received specifc treatment for the disease. Conclusions: Our survey suggests that there are difficulties in the diagnostic approach of ILDs, there is a low percentage of patients that are evaluated in referral centers and there is a low proportion of IPF patients receiving specific treatment

[Pathophysiology of diabetic retinopathy and nephropathy]. / Fisiopatología de la retinopatía y nefropatía diabéticas.

Despite the availability of multiple therapeutic approaches, diabetes mellitus with chronic hyperglycemia remains as the main cause of new cases of blindness and chronic renal failure in the western hemisphere. We herein review the molecular mechanisms by which chronic hyperglycemia causes retinopathy and nephropathy in type I and type 2 diabetic patients. Diabetic retinopathy develops silently along years or decades, producing symptoms only in its very late stages. Its slow development starts with the activation of aldose reductase, shortly followed by the destruction of the retinal pericyte cells, and ends in sudden blindness when vitreous hemorrhage ensues. Nephropathy, on the other hand, centers its pathophysiology in the mesangial cell, that starts as a modified smooth-muscle cell, and turns itself into a myo-fibroblast, produces such amounts of cytoplasm and extracellular protein that strangulates the glomerular capillaries and causes renal failure. After a detailed review of the molecular mechanisms of the aforementioned complications, we conclude that, apart from directing our attention to the emerging medications that are being developed to block these molecular pathways, we should never abandon the struggle for improving the glycemic control of our diabetic patients.

Near-optimal glycemic control in Chilean women with pregestational type-2 diabetes: persistent macrosomia relates to maternal pre-pregnancy overweight.

UNLABELLED: After a 10-year program intending to improve glycemic control in diabetic pregnancies, we evaluated whether factors underlying macrosomia are similar for type-1 and -2 pregestational diabetic women. PATIENTS AND METHODS: Twenty-three pregnancies in type-1 diabetics (PDM1, age 28.3+/-1.1 years) and 51 pregnancies in type-2 diabetics (PDM2, age 32.8+/-0.6 years) were followed and treated with intensified insulin therapy. Several factors potentially influencing macrosomia were evaluated. STATISTICS: chi-square, Fisher's exact, Student's "t" and Mann-Whitney "U" tests, and ROC analysis. RESULTS: In PDM1 and PDM2, respectively, large-for-gestational-age (LGA) frequencies were 26.08% and 37.25% (NS), antepartum HbA1c values were 6.5+/-0.32 and 6.1+/-0.16 (NS), and pre-pregnancy body mass indexes (BMI) were 23.03+/-0.66 and 30.01+/-0.89 (p<0.0001). In PDM1 the main predictor of LGA was an antepartum HbA1c> or =6.8% (p=0.046), whereas in PDM2 pregestational BMI> or =24 the variable associated (p=0.032) with LGA newborns. CONCLUSIONS: PDM1 and PDM2 differ in the underlying factors related to macrosomia. Whereas in PDM1 the antepartum HbA1c emerged as the most significant variable, suggesting that glycemic control largely determines macrosomia, in PDM2 with near-optimal glycemic control, macrosomia related to pregestational BMI.

[Atrial thrombus entrapped in a patent foramen oval. Report of one case]. / Trombo auricular atrapado en el foramen oval: Complicación infrecuente en el tromboembolismo pulmonar.

We report a 63 year-old female with a pulmonary embolism in whom echocardiography revealed the presence of right heart thrombus. A section of this thrombus was entrapped in a patent foramen oval and floating in both atria. This rare situation, named impending paradoxical embolism, prompted us to perform a surgical intervention, removing the thrombus and repairing the foramen ovale.

Fisiopatología de la retinopatía y nefropatía diabéticas / Pathophysiology of diabetic retinopathy and nephropathy

Despite the availability of multiple therapeutic approaches, diabetes mellitus with chronic hyperglycemia remains as the main cause of new cases of blindness and chronic renal failure in the western hemisphere. We herein review the molecular mechanisms by which chronic hyperglycemia causes retinopathy and nephropathy in type I and type 2 diabetic patients. Diabetic retinopathy develops silently along years or decades, producing symptoms only in its very ¡ate stages. Its slow development starts with the activation of aldose reducíase, shortly followed by the destruction of the retinal pericyte cells, and ends in sudden blindness when vitreous hemorrhage ensues. Nephropathy, on the other hand, centers its pathophysiology in the mesangial cell, that starts as a modified smooth-muscle cell, and turns itself into a myo-fibroblast, produces such amounts of cytoplasm and extracellular protein that strangulates the glomerular capillaries and causes renal failure. After a detailed review of the molecular mechanisms of the aforementioned complications, we conclude that, apart from directing our attention to the emerging medications that are being developed to block these molecular pathways, we should never abandon the struggle for improving the glycemic control of our diabetic patients.

Trombo auricular atrapado en el foramen oval: Complicación infrecuente en el tromboembolismo pulmonar / Atrial thrombus entrapped in a patent foramen oval: Report of one case

We report a 63 year-old female with a pulmonary embolism in whom echocardiography revealed the presence ofríght heart thrombus. A section ofthis thrombus was entrapped in a patent foramen oval and floating in both atria. This rare situation, named impending paradoxical embolism, prompted us to perform a surgical intervention, removing the thrombus andrepairing the foramen ovale.