Complex regional pain syndrome in a patient with neuroendocrine tumour under treatment with everolimus.

Everolimus is an immunosuppressant agent used in organ transplantation and, more recently, in cancer therapy. It has demonstrated beneficial effects in breast cancer, renal cancer, and neuroendocrine tumours. However, the treatment is not without side effects, some of which are still little known. We report the case of a 56 year-old man with a diagnosis of neuroendocrine tumour who developed a complex regional pain syndrome (CRPS) secondary to treatment with everolimus. CRPS has been linked to treatments with everolimus in renal and breast cancer patients as well as in renal transplant patients. To our knowledge, this is the first case of CRPS in a neuroendocrine tumour patient on everolimus treatment.

Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Frequency and outcomes of concomitant use of proton pump inhibitors and clopidogrel after hospital discharge.

OBJECTIVE: To assess the frequency of concomitant use of proton pump inhibitors (PPI) in patients treated with clopidogrel, and the potential impact of this use on cardiovascular events. METHOD: Three-month prospective observational study. All patients taking clopidogrel who were admitted to the study hospital were included in the study. They were split into categories based on whether they had taken the drug concomitantly with PPI upon admission, upon discharge or during follow-up, or if they had not taken the two drugs together at all. Any post-discharge readmissions for cardiovascular events in the three months following the original admission were also recorded. RESULTS: A total of 134 patients were included in the study. Only 26 patients (19,6%) did not take any PPI. Among 14 patients (10.5%) readmitted because of a cardiovascular event, 13 were taking clopidogrel concomitantly with a PPI (not statistically significant). Most of the readmitted patients presented other risk factors potentially related with cardiovascular events. CONCLUSION: This study underlines a high concomitant use of PPI with clopidogrel, with no evidence of an increasing risk of readmission due to cardiovascular event potentially related to a drug-drug interaction between these drugs. The study did not identify any readmission related to a gastro-intestinal complication.

An investigation of the resolution of inflammation (catabasis) in COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an enhanced inflammatory response to smoking that persists despite quitting. The resolution of inflammation (catabasis) is a complex and highly regulated process where tissue resident macrophages play a key role since they phagocytose apoptotic cells (efferocytosis), preventing their secondary necrosis and the spill-over of their pro-inflammatory cytoplasmic content, and release pro-resolution and tissue repair molecules, such as TGFß, VEGF and HGF. Because inflammation does not resolve in COPD, we hypothesized that catabasis may be abnormal in these patients. METHODS: To explore this hypothesis, we studied lung tissue samples obtained at surgery from 21 COPD patients, 22 smokers with normal spirometry and 13 non-smokers controls. In these samples we used: (1) immunohistochemistry to assess the expression of CD44, CD36, VEGF and TGFß in lung macrophages; (2) real time PCR to determine HGF, PPARγ, TGFß, VEGF and MMP-9 gene expression; and, (3) ELISA to quantify lipoxin A4, a lipid mediator of catabasis. RESULTS: We found that current and former smokers with COPD showed: (1) more inflammation (higher MMP-9 expression); (2) reduced macrophage surface expression of CD44, a key efferocytosis receptor; and, (3) similar levels of TGFß, VEGF, HGF, PPARγ, and lipoxin A4 than smokers with normal spirometry, despite the presence of inflammation and disease. CONCLUSIONS: These results identify several potential abnormalities of catabasis in patients with COPD.

Anti-tissue antibodies are related to lung function in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a multicomponent disease. Autoimmunity can contribute to the pathogenesis of COPD. OBJECTIVES: This study investigates the prevalence of circulating antinuclear antibodies (ANA) and anti-tissue (AT) antibodies, two common markers of autoimmunity, in COPD and their relationship with several components of the disease. METHODS: We determined lung function, the serum titers of ANA and AT by immunofluorescence, and the serum levels of C-reactive protein (CRP) by high sensitivity nephelometry in 328 patients with clinically stable COPD and in 67 healthy controls recruited in the PAC-COPD study. Multiple linear and logistic regression analysis was used to analyze results. MEASUREMENTS AND MAIN RESULTS: The prevalence of abnormal ANA and AT titers was 34% and 26% in patients and 3% and 6% in controls, respectively. Levels of AT greater than or equal to 1:320 were seen in 21% of patients with COPD and were independently associated with the severity of airflow limitation and gas transfer impairment (P < 0.05). Neither ANA or AT titers was related to body mass index, current smoking status, use of inhaled steroids, the Charlson index, or serum C-reactive protein values. CONCLUSIONS: Between a quarter and a third of patients with clinically stable COPD present abnormal titers of circulating ANA and AT. The observed relationship between AT and lung function supports a role for autoimmunity in the pathogenesis of COPD.

Low erythropoietin plasma levels during exacerbations of COPD.

BACKGROUND: It is known that pro-inflammatory cytokines suppress in vitro the gene expression and protein production of erythropoietin (Epo). We hypothesized that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) may influence Epo production, particularly during episodes of exacerbation of the disease (ECOPD) where an inflammatory burst is known to occur. OBJECTIVES: We compared the plasma levels of Epo and high-sensitivity (hs) C-reactive protein (hsC-RP) in patients hospitalized because of ECOPD (n = 26; FEV(1): 48 +/- 15% predicted), patients with clinically stable COPD (n = 31; FEV(1): 49 +/- 17% predicted), smokers with normal lung function (n = 9), and healthy never smokers (n = 9). METHODS: Venous blood samples were taken between 9 and 10 a.m. after an overnight fast into tubes with EDTA (10 ml) or without EDTA (10 ml). Plasma levels of Epo (R&D Systems Inc., Minneapolis, Minn., USA) and hsC-RP (BioSource, Belgium) were determined by ELISA. RESULTS: Log-Epo plasma levels were significantly lower (0.46 +/- 0.32 mU/ml) in ECOPD than in stable COPD (1.05 +/- 0.23 mU/ml), smokers (0.95 +/- 0.11 mU/ml) and never smokers with normal lung function (0.92 +/- 0.19 mU/ml) (p < 0.01, each). In a subset of 8 COPD patients who could be studied both during ECOPD and clinical stability, log-Epo increased from 0.49 +/- 0.42 mU/ml during ECOPD to 0.97 +/- 0.19 mU/ml during stability (p < 0.01). In patients with COPD log-Epo was significantly related to hsC-RP (r = -0.55, p < 0.0001) and circulating neutrophils (r = -0.48, p < 0.0001). CONCLUSIONS: These results show that the plasma levels of Epo are reduced during ECOPD likely in relation to a burst of systemic inflammation.

Abnormal levels of circulating endothelial progenitor cells during exacerbations of COPD.

Cardiovascular morbidity and mortality is increased in patients with chronic obstructive pulmonary disease (COPD). Reduced levels of circulating endothelial progenitor cells (EPCs) are associated with increased risk of death in patients with stable coronary artery disease (CAD). Likewise, during acute events of CAD, the number of circulating EPCs increases under the influence of vascular endothelial growth factor (VEGF) and systemic inflammation. Abnormal levels of circulating EPCs have been reported in patients with COPD. However, the response of EPCs to episodes of exacerbation of the disease (ECOPD) has not been investigated yet. We hypothesized that similar to what occurs during acute events of CAD, levels of circulating EPCs would increase during ECOPD. We compared levels of circulating EPCs (assessed by the % of CD34(+)KDR(+) cells determined by flow cytometry) in patients hospitalized because of ECOPD (n = 35; 65 +/- 9 years [mean +/- SD]; FEV(1) = 46 +/- 15% predicted), patients with stable COPD (n = 44; 68 +/- 8 years; FEV(1) = 49 +/- 17% predicted), smokers with normal lung function (n = 10; 60 +/- 9 years), and healthy never smokers (n = 10; 62 +/- 4 years). To investigate potential mechanisms of EPC regulation, we assessed both VEGF and high-sensitivity C-reactive protein (hsC-RP) in plasma. Our results show that EPC levels were higher (p < 0.05) in patients with ECOPD (1.46 +/- 1.63%) than in those with stable disease (0.68 +/- 0.83%), healthy smokers (0.65 +/- 1.11%), and healthy never smokers (1.05 +/- 1.36%). The percentage of circulating EPCs was positively related to VEGF plasma levels during ECOPD (r = 0.51, p = 0.003). In a subset of 12 patients who could be studied during both ECOPD and clinical stability, the EPCs levels increased during ECOPD. We conclude that EPC levels are increased during ECOPD, likely in relation to VEGF upregulation.

CSF sAPPß, YKL-40, and neurofilament light in frontotemporal lobar degeneration.

OBJECTIVE: To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD). METHODS: We analyzed 3 CSF biomarkers (YKL-40, soluble ß fragment of amyloid precursor protein [sAPPß], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (ß-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility. RESULTS: Patients with FTLD-related syndromes had lower levels of sAPPß than CN and patients with AD. The levels of sAPPß showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPß/YKL-40 and NfL/sAPPß ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD. CONCLUSIONS: The combination of sAPPß with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF levels of sAPPß, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.

Lack of Correlation Between Pulmonary and Systemic Inflammation Markers in Patients with Chronic Obstructive Pulmonary Disease: A Simultaneous, Two-Compartmental Analysis. / Ausencia de correlación entre marcadores de inflamación pulmonar y sistémica en pacientes con enfermedad pulmonar obstructiva crónica: un análisis bi-compartimental simultáneo.

INTRODUCTION: The origin of systemic inflammation in chronic obstructive pulmonary disease (COPD) patients remains to be defined, but one of the most widely accepted hypothesis is the 'spill over' of inflammatory mediators from the lung to the circulation. OBJECTIVE: To evaluate the relationship between pulmonary and systemic inflammation in COPD quantifying several inflammatory markers in sputum and serum determined simultaneously. METHODOLOGY: Correlations between various inflammatory variables (TNF-α, IL6, IL8) in sputum and serum were evaluated in 133 patients from the PAC-COPD cohort study. A secondary objective was the evaluation of relationships between inflammatory variables and lung function. RESULTS: Inflammatory markers were clearly higher in sputum than in serum. No significant correlation was found (absolute value, r=0.03-0.24) between inflammatory markers in blood and in sputum. There were no significant associations identified between those markers and lung function variables, such as FEV1, DLCO and PaO2 neither. CONCLUSIONS: We found no correlation between pulmonary and systemic inflammation in patients with stable COPD, suggesting different pathogenic mechanisms.

Effects of simvastatin in chronic obstructive pulmonary disease: Results of a pilot, randomized, placebo-controlled clinical trial.

INTRODUCTION: Statins may have pleiotropic effects in COPD, but mechanisms remain unclear. OBJECTIVES: To assess the pleiotropic effect of statins in patients with stable COPD on (1): lung function (2); pulmonary and systemic inflammation (3); endothelial function (vascular stiffness) and circulating vascular growth factors; and (4), serum uric acid levels. METHOD: Pilot, double-blind, randomized, placebo-controlled clinical trial in 24 patients with stable COPD, all statin-naïve, who were randomized (1:1) to receive simvastatin 40 mg/24 h during 12 weeks (n = 12; 69.0 ± 7.3 years; post-bd FEV1 53.4 ± 10.0% pred.) or placebo (n = 12; 66.4 ± 4.6 years; post-bd FEV1 48.2 ± 12.6% pred.). Nine patients per group (total n = 18) completed the study. RESULTS: Lung function, pulmonary and systemic inflammatory markers and the degree of vascular stiffness did not change significantly in any group. However, treatment with simvastatin increased the plasma levels of erythropoietin (Epo) (4.2 ± 2.2 mIU/mL to 6.8 ± 3.2 mlU/mL, p < 0.05) and reduced those of serum uric acid (7.1 ± 1.3 mg/dL to 6.5 ± 1.4 mg/dL, p < 0.01). CONCLUSIONS: Short-term treatment with simvastatin in stable COPD patients did not modify lung function, pulmonary and systemic inflammation, or vascular stiffness, but it changed Epo and uric acid levels.

The inflammasome pathway in stable COPD and acute exacerbations.

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1ß mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1ß, IL-18) were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD.

Expression of adhesion molecules during apoptosis of circulating neutrophils in COPD.

STUDY OBJECTIVES: Neutrophil accumulation occurs in the lungs of patients with COPD. This can be due to increased recruitment and/or delayed tissue clearance. Previous studies have described alterations in circulating neutrophils in these patients that can facilitate the former. Dysregulation of neutrophil apoptosis may contribute to the latter. This study investigated the potential abnormalities of the apoptotic process in COPD patients. DESIGN: Prospective study. SETTINGS: Outpatient clinic in a urban, tertiary hospital. PATIENTS: Fourteen stable patients with COPD, 8 smokers with normal lung function, and 8 healthy nonsmoking subjects. MEASUREMENTS AND RESULTS: We cultured circulating neutrophils that had been harvested from the study subjects at 2, 6, and 24 h. Apoptosis was assessed using flow cytometry by annexin binding and CD16 expression. The surface expression of the adhesion molecules Mac-1 (CD11b) and L-selectin (CD62L) also was determined by flow cytometry. The percentage of apoptotic neutrophils increased with time similarly in all groups. However, the surface expression of Mac-1 (CD11b) was higher, and that of L-selectin (CD62L) was lower, during apoptosis in the neutrophils of patients with COPD. CONCLUSIONS: These results show that, quantitatively, in vitro neutrophil apoptosis in COPD patients occurred at a rate similar to that found in healthy individuals and smokers with normal lung function. Qualitatively, however, the increased surface expression of Mac-1 (CD11b) and the decreased surface expression of L-selectin (CD62L) observed in the apoptotic neutrophils of COPD patients indicate increased activation during the apoptotic process. This may be relevant for the pathogenesis of COPD.

Differential response of lymphocytes and neutrophils to high intensity physical activity and to vitamin C diet supplementation.

We have determined the effects of chronic vitamin C intake on neutrophil and lymphocyte antioxidant defences during the acute phase immune response induced by intense exercise. Blood samples were taken from 16 voluntary athletes in basal conditions, both immediately after and 1 h after a duathlon competition. Sportsmen's nutrient intakes were determined before the competition. After determining the basal plasmatic ascorbate levels, the results were analysed taking into account the vitamin C intake and their plasmatic levels. Two groups were constituted, the vitamin C supplemented group and the control group, with the dietary vitamin C intake as the only statistical difference between groups. The duathlon competition induced a significant neutrophilia, which was higher in the supplemented group. Lymphocyte antioxidant enzyme activities increased after the competition, with a higher increase in SOD activity in the control group than in the supplemented one. The competition decreased neutrophil antioxidant enzyme activities and neutrophil ascorbate concentration. The decrease in the SOD activity in the supplemented group was higher than in the control group. Finally, the duathlon competition increased the expression of MAC-1 neutrophil adhesion molecule in the supplemented group. High vitamin C intake influenced the response of neutrophils and lymphocytes to oxidative stress induced by exercise, increasing the neutrophil activation.

Oxidative stress in mothers who have conceived fetus with neural tube defects: the role of aminothiols and selenium.

BACKGROUND & AIMS: Methionine metabolic impairment and selenium deficit have been associated to neural tube defects. The relationship between thiol metabolism and selenium is not well known. We assessed the status of aminothiols and selenium, as well as thiolic status and the amino acids involved in arginine synthesis in the case of selenium depletion and repletion, studying their relationship to neural tube defects. METHODS: We studied 44 women of 37 +/- 8 years (mean +/- SD) who had conceived fetuses with neural tube defects as cases; and 181 women of 39 +/- 7 years (mean +/- SD) with healthy children as controls. We determined selenium, vitamin B12, serum folates, plasma thiol compounds and amino acids. Homocysteine transsulfuration was assessed using total cysteine/total homocysteine ratio (tCys/tHcy), and selenium repletion cut-off value was 1.06 micromol/l (84 microg/l). RESULTS: Cases showed significantly lower levels (median) than controls of total homocysteine (P = 0.001), total cysteinylglycine (P < 0.001), selenium (P < 0.001) and tryptophane (P = 0.002); and higher tCys/tHcy levels (P < 0.001), glutathione (P = 0.008) and L-arginine (P = 0.001). Cases with selenium depletion (selenium < or = 1.06 micromol/l) had significantly higher levels than controls of cysteine (P = 0.010), glutathione (P = 0.005), tCys/tHcy (P < 0.001), and arginine (P = 0.004), but significantly lower levels than controls of tryptophane (P = 0.027), cysteinylglycine (P < 0.001) and folates (P < 0.001). Only cysteinylglycine was lower than controls (P < 0.001) when selenium > 1.06 micromol/l. Methionine levels were higher in cases with selenium depletion than in repletion (P = 0.029). CONCLUSIONS: According to our data, a diet deficient in selenium and folates or their absorption impairment, and/or other mechanisms related to polyamines and nitric oxide can lead to oxidant/antioxidant imbalance and to a higher occurrence of these malformations.

Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE.

Blood samples are extensively used for the molecular diagnosis of many hematological diseases. The daily practice in a clinical laboratory of molecular diagnosis in hematology involves using a variety of techniques, based on the amplification of nucleic acids. Current methods for polymerase chain reaction (PCR) use purified genomic DNA, mostly isolated from total peripheral blood cells or white blood cells (WBC). In this paper we describe a real-time fluorescence resonance energy transfer-based method for genotyping directly from blood cells. Our strategy is based on an initial isolation of the WBCs, allowing the removal of PCR inhibitors, such as the heme group, present in the erythrocytes. Once the erythrocytes have been lysed, in the LightCycler(®) 2.0 Instrument, we perform a real-time PCR followed by a melting curve analysis for different genes (Factors 2, 5, 12, MTHFR, and HFE). After testing 34 samples comparing the real-time crossing point (CP) values between WBC (5×10(6) WBC/mL) and purified DNA (20 ng/µL), the results for F5 Leiden were as follows: CP mean value for WBC was 29.26±0.566 versus purified DNA 24.79±0.56. Thus, when PCR was performed from WBC (5×10(6) WBC/mL) instead of DNA (20 ng/µL), we observed a delay of about 4 cycles. These small differences in CP values were similar for all genes tested and did not significantly affect the subsequent analysis by melting curves. In both cases the fluorescence values were high enough, allowing a robust genotyping of all these genes without a previous DNA purification/extraction.

Molecular mechanisms of inflammation during exacerbations of chronic obstructive pulmonary disease.

INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known. OBJECTIVES: To explore the inflammatory changes and possible mechanisms during COPD exacerbation. METHODS: We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1ß, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls. RESULTS: COPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function. CONCLUSIONS: Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.

Ausencia de correlación entre marcadores de inflamación pulmonar y sistémica en pacientes con enfermedad pulmonar obstructiva crónica: un análisis bi-compartimental simultáneo / Lack of Correlation Between Pulmonary and Systemic Inflammation Markers in Patients with Chronic Obstructive Pulmonary Disease: A Simultaneous, Two-Compartmental Analysis

Introducción: El origen de la inflamación sistémica en pacientes con enfermedad pulmonar obstructiva crónica (EPOC) es poco conocido, y una de las hipótesis más aceptadas es el paso de la inflamación del pulmón a la sangre (spill-over). Objetivo: Evaluar la relación entre la inflamación pulmonar y sistémica en la EPOC mediante la cuantificación de diversos marcadores inflamatorios en esputo y suero obtenidos en el mismo individuo de forma simultánea. Metodología: De 133 pacientes de la cohorte PAC-EPOC se evaluaron las relaciones entre diferentes variables inflamatorias (TNFα, IL-6, IL-8) en suero y esputo. Como objetivo secundario se evaluaron las relaciones de las variables inflamatorias de suero con la función pulmonar. Resultados: Los valores de los marcadores inflamatorios fueron claramente superiores en esputo que en suero. No se hallaron correlaciones relevantes (en valor absoluto, r = 0,03-0,24) entre los marcadores inflamatorios en sangre y en esputo. Tampoco se identificaron asociaciones significativas entre dichos marcadores, con variables de función pulmonar como el FEV1, DLCO y la PaO2. Conclusiones: En pacientes con EPOC estable no existe correlación entre la inflamación pulmonar y sistémica, lo que sugiere mecanismos patogénicos diferentes

Introduction: The origin of systemic inflammation in chronic obstructive pulmonary disease (COPD) patients remains to be defined, but one of the most widely accepted hypothesis is the ‘spill over’ of inflammatory mediators from the lung to the circulation. Objective: To evaluate the relationship between pulmonary and systemic inflammation in COPD quantifying several inflammatory markers in sputum and serum determined simultaneously. Methodology: Correlations between various inflammatory variables (TNF-α, IL6, IL8) in sputum and serum were evaluated in 133 patients from the PAC-COPD cohort study. A secondary objective was the evaluation of relationships between inflammatory variables and lung function. Results: Inflammatory markers were clearly higher in sputum than in serum. No significant correlation was found (absolute value, r = 0.03-0.24) between inflammatory markers in blood and in sputum. There were no significant associations identified between those markers and lung function variables, such as FEV1, DLCO and PaO2 neither. Conclusions: We found no correlation between pulmonary and systemic inflammation in patients with stable COPD, suggesting different pathogenic mechanisms

Pulmonary and systemic hepatocyte and keratinocyte growth factors in patients with chronic obstructive pulmonary disease.

BACKGROUND: The potential role of growth factors in chronic obstructive pulmonary disease (COPD) has begun to be addressed only recently and is still poorly understood. For this study, we investigated potential abnormalities of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in patients with COPD. METHODS: To this end, we compared the levels of HGF and KGF, measured by enzyme-linked immunosorbent assay (ELISA), in bronchoalveolar lavage (BAL) fluid and in serum in 18 patients with COPD (62 +/- 9 yrs, forced expiratory volume in one second [FEV1] 57 +/- 12% ref, X +/- standard deviation of mean), 18 smokers with normal lung function (58 +/- 8 yrs, FEV1 90 +/- 6% ref) and 8 never smokers (67 +/- 9 yrs, 94 +/- 14% ref). RESULTS: We found that in BAL, HGF levels were higher in patients with COPD than in the other two groups whereas, in serum, HGF concentration was highest in smokers with normal lung function (p < 0.01). KGF levels were not significantly different between groups, neither in blood nor in BAL (most values were below the detection limit). CONCLUSIONS: These results highlight a different response of HGF in BAL and serum in smokers with and without COPD that may be relevant for tissue repair in COPD.

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease.

OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. PATIENTS AND METHODS: To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 +/- 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 +/- 5% ref). RESULTS: We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. CONCLUSIONS: This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1beta, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.

Mecanismos moleculares de inflamación durante las agudizaciones de la enfermedad pulmonar obstructiva crónica / Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

Introducción: Las agudizaciones de la enfermedad pulmonar obstructiva crónica (AEPOC) se caracterizanpor una respuesta inflamatoria pulmonar y sistémica, que persiste tiempo después de la resolución clínica.Los mecanismos de este proceso inflamatorio no son bien conocidos.Objetivos: Investigar los cambios inflamatorios y sus mecanismos durante las agudizaciones de la EPOC.Métodos: Se determinaron las concentraciones de células inflamatorias en sangre y esputo, óxido nítricoen aire exhalado (FeNO), proteína C reactiva (PCR) en plasma, citocinas (interleucinas [IL] 6, 8, 1 , 10,12, TNF- ) y SLPI (inhibidor de la leucoproteasa), marcadores de estrés oxidativo, la actividad del factornuclear kappa B (NF- B) y de la enzima histona deacetilasa (HDAC) a 17 pacientes durante una AEPOC,en fase estable y a 17 controles fumadores y 11 no fumadores.Resultados: Las AEPOC se caracterizaron por presentar niveles elevados de FeNO (p < 0,05), PCR en plasma(p < 0,001) e IL-8, IL-1 , IL-10 en esputo (p < 0,05) y mayor activación de NF- B en macrófagos de esputoen comparación con EPOC estable y controles. Durante la fase estable persisten niveles elevados de estrésoxidativo, SLPI, IL-8, IL-6 y TNF-alfa, sin objetivarse cambios en la actividad HDAC ni en la cantidad deneutrófilos en esputo a pesar de presentar una mejoría significativa (p < 0,05) de la función pulmonar.Conclusiones: Durante las AEPOC se observan cambios en marcadores inflamatorios pulmonares y sistémicosque no se resuelven por completo en fase estable. El tratamiento actual no permite modificar laactividad HDAC lo que limita sus efectos antiinflamatorios(AU)

Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory andsystemic response that increases during exacerbations of the disease (ECOPD), although the mechanismsof this inflammatory process are not well known.Objectives: To explore the inflammatory changes and possible mechanisms during ECOPD.Methods: We determined the inflammatory cell concentrations in blood and sputum, nitric oxide inexhaled air (FeNO), reactive C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1 , 10, 12, TNF- )and SLPI and total antioxidant activity (TAS) in blood and sputum, the activity of nuclear kappa B factor(NF-kB) and of the histone deacetylase enzymes (HDAC) in 17 patients during ECOPD, in stable phase andin 17 smoking controls and 11 non- smoking.Results: ECOPD is characterised by higher levels of FeNO (P<.05), plasma CRP (P<.001) and IL-8, IL-1B,IL-10 in sputum (P<.05) compared with stable COPD and controls. The TAS levels in sputum were lowerin the exacerbated than in stable phase (P<.05) although significantly higher than the controls (P<.05). These findings were accompanied by a greater activation of NF-kB in sputum macrophages during theECOPD with no changes in the HDAC activity or in the number of neutrophils in sputum, and a statisticallysignificant deterioration (P<.05) of lung function.Conclusions: Changes were observed in different pulmonary and systemic inflammatory markers duringECOPD, that were not completely resolved during stability. However, current treatment does not allowthe modification of HDAC activity, which limits its anti-inflammatory effects(AU)