Role of Telomere Length in Survival of Patients with Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases.

Interstitial lung diseases (ILDs) constitute a group of more than 200 disorders, with idiopathic pulmonary fibrosis (IPF) being one of the most frequent. Telomere length (TL) shortening causes loss of function of the lung parenchyma. However, little is known about its role as a prognostic factor in ILD patients. With the aim of investigating the role of TL and telomerase activity in the prognosis of patients affected by ILDs, we analysed lung tissue samples from 61 patients. We measured relative TL and telomerase activity by conventional procedures. Both clinical and molecular parameters were associated with overall survival by the Kaplan-Meier method. Patients with IPF had poorer prognosis than patients with other ILDs (p = 0.034). When patients were classified according to TL, those with shortened telomeres reported lower overall survival (p = 0.085); differences reached statistical significance after excluding ILD patients who developed cancer (p = 0.021). In a Cox regression analysis, TL behaved as a risk-modifying variable for death associated with rheumatic disease (RD) co-occurrence (p = 0.029). Also, in patients without cancer, ferritin was significantly increased in cases with RD and IPF co-occurrence (p = 0.032). In relation to telomerase activity, no significant differences were detected. In conclusion, TL in lung tissue emerges as a prognostic factor in ILD patients. Specifically, in cases with RD and IPF co-occurrence, TL can be considered as a risk-modifying variable for death.

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs / Ensayo piloto de conservación pulmonar hipotérmica prolongada para analizar la lesión de isquemia-reperfusión en cerdos

Background: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. Methods: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. Results: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1β and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. (AU)

Antecedentes: En el trasplante de pulmón (TP), la duración del tiempo de isquemia es controvertida, ya que se estableció de forma arbitraria. Sería útil explorar el impacto del tiempo de isquemia fría (TIF) prolongado sobre la lesión de isquemia-reperfusión en un modelo experimental. Métodos: Ensayo piloto experimental aleatorizado de grupos paralelos y análisis ciego final utilizando un modelo de TP en cerdos. Se extrajeron los órganos de los animales donantes (n=8). Los pulmones se conservaron durante 6 horas (n=4) o 12 horas (n=4) en hipotermia aeróbica. El pulmón izquierdo se trasplantó y reperfundió durante 4 horas. Se obtuvieron biopsias de pulmón (i) al comienzo del TIF, (ii) al final del TIF, (iii) 30 minutos después de la reperfusión y (iv) 4 horas después de la reperfusión. Los injertos de pulmón se evaluaron histológicamente mediante la puntuación de daño histológico pulmonar y la relación de peso húmedo y peso seco. La respuesta inflamatoria se valoró mediante la determinación de citoquinas inflamatorias. Se determinó la actividad de caspasa-3 como marcador de apoptosis. Resultados: No observamos diferencias en la puntuación de daño histológico pulmonar o en la relación de peso húmedo y peso seco en un momento dado entre los pulmones sometidos a 6 h-TIF o 12 h-TIF. Las IL-1β e IL-6 mostraron una tendencia ascendente durante la reperfusión en ambos grupos. El TNF-α alcanzó su punto máximo dentro de los 30 minutos posteriores a la reperfusión. Apenas se detectó IFN-γ. La inmunoexpresión de caspasa-3 se clasificó semicuantitativamente por el porcentaje de células teñidas. Se observó un 20% de células apoptóticas 30 minutos después de la reperfusión. (AU)

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs.

BACKGROUND: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. METHODS: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. RESULTS: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1ß and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. CONCLUSIONS: We observed that 6 and 12h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.

Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs.

BACKGROUND: In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model. METHODS: Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n=8) were submitted to organ procurement. Lungs were subjected to 6h (n=4) or 12h (n=4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30min after reperfusion, and (iv) 4h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker. RESULTS: We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6h-CIT or 12h-CIT. IL-1ß and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30min after reperfusion. CONCLUSIONS: We observed that 6 and 12h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.

Combined Hepatic and Pulmonary Metastasectomies From Colorectal Carcinoma. Data From the Prospective Spanish Registry 2008-2010 / Metastasectomías hepáticas y pulmonares combinadas de carcinoma colorrectal. Datos del registro prospectivo español 2008-2010

Introduction: Resection of both liver and lung metastases from colorectal carcinoma (CRC) is a standard of care in selected patients with oligometastatic disease. We present here the analysis of the subgroup of patients undergoing combined surgery from the Spanish Group of Surgery of Pulmonary Metastases (PM) from Colorectal Carcinoma (GECMP-CCR-SEPAR). Methods: We analyze characteristics, survival and prognostic factors of patients undergoing combined resection from March-2008 to February-2010 and followed-up during at least 3 years, from the prospective multicenter Spanish Registry. Results: A total of 138 patients from a whole series of 543 cases from 32 thoracic surgery units underwent both procedures. Seventy-seven (43.8%) resected liver metastases were synchronic with colorectal tumor. Median disease specific survival (DSS) from first pulmonary metastasectomy was 48.9 months, being three and 5-year DSS 65.1% and 41.7%, respectively. From CRC-surgery median DSS was 97.2 months, with 3 and 5-year DSS rates of 96.7% and 77%, respectively. Five-year DSS from pulmonary metastasectomy was 41.7% for patients with combined resection and 52.4% for those without hepatic involvement (P = .04). Differences disappeared when considering DSS from colorectal surgery. Carcinoembrionary antigen (CEA) before lung surgery over 10 mg/dl and bilateral PM were independent prognostic factors for survival (hazard ratio 2.4 and 2.5, respectively). Conclusions: Patients with resection of PM of CRC with history of resected hepatic metastases presented significantly lower disease specific survival rates than those undergoing pulmonary metastasectomy alone. CEA before lung surgery and bilateral PM associated worse prognosis

Introducción: La resección de metástasis hepáticas y pulmonares del carcinoma colorrectal (CCR) es un tratamiento estándar para determinados pacientes con enfermedad oligometastásica. Presentamos el análisis del subgrupo de pacientes sometidos a cirugía combinada del Grupo Español de Cirugía de Metástasis Pulmonares (MP) de Carcinoma Colorrectal (GECMP-CCR-SEPAR). Métodos: Analizamos las características, la supervivencia y los factores pronósticos de los pacientes sometidos a resección combinada desde marzo de 2008 a febrero de 2010, con seguimiento durante al menos 3 años en el Registro Español, prospectivo y multicéntrico. Resultados: Se sometieron a ambos procedimientos 138 pacientes de una serie completa de 543 casos, procedentes de 32 unidades de cirugía torácica. Setenta y siete (43,8%) de las metástasis hepáticas resecadas eran sincrónicas al tumor colorrectal. La mediana de la supervivencia específica para la enfermedad (SEE) desde la primera metastasectomía pulmonar fue de 48,9 meses; las SEE a 3 y 5 años fueron del 65,1 y 41,7%, respectivamente. La mediana de la SEE desde la cirugía del CCR fue de 97,2 meses, con tasas de la SEE a 3 y 5 años del 96,7 y 77%, respectivamente. Las SEE a 5 años de la metastasectomía pulmonar fueron del 41,7% para los pacientes con resección combinada y del 52,4% para aquellos sin afectación hepática (p = 0,04). Las diferencias desaparecieron cuando se tenía en cuenta la SEE desde la cirugía colorrectal. Tener un nivel de antígeno carcinoembrionario (ACE) por encima de 10mg/dl antes de la cirugía pulmonar y la presencia bilateral de MP fueron factores pronósticos independientes para la supervivencia (odds ratio: 2,4 y 2,5, respectivamente). Conclusiones: Los pacientes con resección de MP de CCR con antecedentes de metástasis hepáticas resecadas presentaron tasas de SEE significativamente más bajas que aquellos sometidos a metastasectomía pulmonar sola. El ACE antes de la cirugía pulmonar y la presencia de MP bilaterales se asociaron a peor pronóstico

Combined Hepatic and Pulmonary Metastasectomies From Colorectal Carcinoma. Data From the Prospective Spanish Registry 2008-2010.

INTRODUCTION: Resection of both liver and lung metastases from colorectal carcinoma (CRC) is a standard of care in selected patients with oligometastatic disease. We present here the analysis of the subgroup of patients undergoing combined surgery from the Spanish Group of Surgery of Pulmonary Metastases (PM) from Colorectal Carcinoma (GECMP-CCR-SEPAR). METHODS: We analyze characteristics, survival and prognostic factors of patients undergoing combined resection from March-2008 to February-2010 and followed-up during at least 3 years, from the prospective multicenter Spanish Registry. RESULTS: A total of 138 patients from a whole series of 543 cases from 32 thoracic surgery units underwent both procedures. Seventy-seven (43.8%) resected liver metastases were synchronic with colorectal tumor. Median disease specific survival (DSS) from first pulmonary metastasectomy was 48.9 months, being three and 5-year DSS 65.1% and 41.7%, respectively. From CRC-surgery median DSS was 97.2 months, with 3 and 5-year DSS rates of 96.7% and 77%, respectively. Five-year DSS from pulmonary metastasectomy was 41.7% for patients with combined resection and 52.4% for those without hepatic involvement (P=.04). Differences disappeared when considering DSS from colorectal surgery. Carcinoembrionary antigen (CEA) before lung surgery over 10mg/dl and bilateral PM were independent prognostic factors for survival (hazard ratio 2.4 and 2.5, respectively). CONCLUSIONS: Patients with resection of PM of CRC with history of resected hepatic metastases presented significantly lower disease specific survival rates than those undergoing pulmonary metastasectomy alone. CEA before lung surgery and bilateral PM associated worse prognosis.

Estado nutricional, indicadores antropométricos y homocisteína sérica en mujerees posmenopáusicas venezolanas / Nutritional status, anthropometric index and serum omocysteine in postmenopausal Venezuelan women

Menopause is associated with an increased body weight and changes in fat distribution, high levels of homocysteine and cardiovascular risk factors associated with estrogen deficiency. The objective was to evaluate body mass index (BMI), waist circumference (WC), waist/hip index (WHI), and serum homocysteine (Hct) levels in postmenopausal women (n 128). Nutritional status was diagnosed by BMI (WHO), WC (normal <88cm, at risk> 88cm), WHI (normal <0.8, at risk> 0.8), serum homocysteine (Hct) (ELISA) normal < 10 mmol/L, at risk >10-15mmol/L, high >15mmol/L and estradiol (ELISA) <65pg/mL (menopause). Sixty five point nine percent were overweight/obese, 47.3 percent and 82.2 percent showed cardio metabolic risk by WC and WHI. There was a significant difference for WHI, and a positive significant correlation between anthropometrics indexes. Ten percent showed risk and hyperhomocysteinaemia, but it was not correlated with the evaluated variables. The subjects had a high frequency of overweight, obesity and android fat distribution, showing a high risk for cardiometabolics diseases.

La menopausia se asocia a un aumento del peso corporal y a cambios en la distribución de grasa, describiéndose también niveles elevados de homocisteína, factores de riesgo cardiovascular asociados al déficit de estrógenos. El objetivo de este estudio fue evaluar índice de masa corporal (IMC), la circunferencia de cintura (CCi), el índice cintura-cadera (ICC), la homocisteína sérica en mujeres posmenopáusicas (n: 128). El diagnóstico nutricional antropométrico se determinó según IMC (OMS); se determinaron la CCi (normal <88cm, en riesgo >88cm), ICC (normal <0,8, en riesgo >0,8), homocisteína sérica (tHci) (ELISA): normal < 10mmol/L, en riesgo >10-15mmol/L, alta: >15mmol/L y estradiol (ELISA): <65pg/mL (posmenopausia). 65,9 por ciento presentaron sobrepeso/ obesidad. 47,3 por ciento y 82,2 por ciento en riesgo cardiometabólico según CCi e ICC. Hubo diferencia significativa para ICC y correlación positiva significativa entre indicadores antropométricos. 10 por ciento presentó riesgo e hiperhomocisteinemia. Este aminoácido no correlacionó con las variables evaluadas. Las mujeres evaluadas presentaron una alta frecuencia de sobrepeso-obesidad y una distribución de grasa tipo androide, presentando un alto riesgo para enfermedades cardiometabólicas.